US5273760A - Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer - Google Patents

Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer Download PDF

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US5273760A
US5273760A US07/814,111 US81411191A US5273760A US 5273760 A US5273760 A US 5273760A US 81411191 A US81411191 A US 81411191A US 5273760 A US5273760 A US 5273760A
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active agent
therapeutically active
dosage form
controlled release
beads
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US07/814,111
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Benjamin Oshlack
Frank Pedi, Jr.
Mark Chasin
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Purdue Pharma LP
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Euro Celtique SA
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Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Priority to US07/814,111 priority Critical patent/US5273760A/en
Assigned to EUROCELTIQUE, S.A. reassignment EUROCELTIQUE, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHASIN, MARK, PEDI, FRANK, JR., OSHLACK, BENJAMIN
Priority to NZ241660A priority patent/NZ241660A/en
Priority to IN121CA1992 priority patent/IN173974B/en
Priority to ZA921366A priority patent/ZA921366B/en
Priority to CA002061824A priority patent/CA2061824C/en
Priority to IL10108092A priority patent/IL101080A/en
Priority to MX9200932A priority patent/MX9200932A/en
Priority to IE079592A priority patent/IE920795A1/en
Priority to JP4071808A priority patent/JP3061474B2/en
Priority to FI921548A priority patent/FI921548A/en
Priority to DE69231415T priority patent/DE69231415T2/en
Priority to PT92106519T priority patent/PT548448E/en
Priority to AT92106519T priority patent/ATE196079T1/en
Priority to EP92106519A priority patent/EP0548448B1/en
Priority to DK92106519T priority patent/DK0548448T3/en
Priority to SG1996005933A priority patent/SG44703A1/en
Priority to ES92106519T priority patent/ES2152221T3/en
Priority to YU42792A priority patent/YU48345B/en
Priority to KR1019920010356A priority patent/KR100252188B1/en
Priority to IN462CA1992 priority patent/IN173298B/en
Priority to BR929202982A priority patent/BR9202982A/en
Priority to AU30024/92A priority patent/AU652871B2/en
Priority to NO19925016A priority patent/NO312577B1/en
Priority to EG80192A priority patent/EG20083A/en
Priority to US08/081,618 priority patent/US5472712A/en
Application granted granted Critical
Publication of US5273760A publication Critical patent/US5273760A/en
Priority to IN455CA1994 priority patent/IN177789B/en
Priority to IN900CA1994 priority patent/IN178679B/en
Priority to US08/508,246 priority patent/US5968551A/en
Priority to US08/561,829 priority patent/US5958459A/en
Priority to US08/667,052 priority patent/US5681585A/en
Priority to IN1452CA1996 priority patent/IN182215B/en
Priority to US08/899,924 priority patent/US6129933A/en
Assigned to PURDUE PHARMA LP reassignment PURDUE PHARMA LP ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EURO-CELTIQUE, S.A.
Priority to HK98104870A priority patent/HK1005686A1/en
Priority to US09/390,719 priority patent/US6294195B1/en
Priority to US09/469,478 priority patent/US6316031B1/en
Priority to GR20000402654T priority patent/GR3034951T3/en
Priority to US09/891,882 priority patent/US6572885B2/en
Priority to US10/054,726 priority patent/US6905709B2/en
Priority to US10/392,586 priority patent/US7270831B2/en
Priority to US10/731,678 priority patent/US20040121001A1/en
Priority to US10/871,251 priority patent/US7316821B2/en
Priority to US11/840,452 priority patent/US20080181941A1/en
Priority to US11/856,610 priority patent/US20080044482A1/en
Priority to US11/983,173 priority patent/US20080063712A1/en
Priority to US12/207,702 priority patent/US20090068269A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • Controlled release formulations known in the art include specially coated beads or pellets, coated tablets and ion exchange resins, wherein the slow release of the active drug is brought about through selective breakdown of, or permeation through, the coating of the preparation or through formulation with a special matrix to affect the release of the drug.
  • the stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, pharmaceutical, and toxicological properties when stored, i.e., in a particular container and environment. Stability study requirements are covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as well as in New Drug Applications (NDAs) and Investigational New Drug Applications (INDs).
  • GMPs Good Manufacturing Practices
  • NDAs New Drug Applications
  • INDs Investigational New Drug Applications
  • sustained release dosage formulations often present special problems with regard to their physical stability during storage.
  • waxes which have been used in such formulations are known to undergo physical alterations on prolonged standing, thus precautions are taken to stabilize them at the time of manufacture or to prevent the change from occurring.
  • Fats and waxy materials when used in purified states are known to crystallize in unstable forms, causing unpredictable variations in availability rates during stability testing at the time of manufacture and during later storage.
  • the moisture content of the product can also influence the stability of the product. Changes in the porosity and/or hydration level of a polymeric film, such as the ethyl celluloses, can alter the rate of water permeation and drug availability. Also, binders such as acacia are known to become less soluble when exposed to moisture and heat. Such problems have been handled by controls in the processing method and proper packaging of the product.
  • Hydrophobic polymers such as certain cellulose derivatives, zein, acrylic resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic acids have been used in the prior art to develop controlled release dosage forms.
  • Methods of using these polymers to develop controlled release dosage forms such as tablets, capsules, suppositories, spheroids, beads or microspheres are to overcoat the individual dosage units with these hydrophobic polymers. It is known in the prior art that these hydrophobic coatings can be applied either from a solution, suspension or dry. Since most of these polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) and evaporating off the solvent.
  • Aqueous dispersions of hydrophobic polymers have been used in the prior art to coat pharmaceutical dosage forms for aesthetic reasons such as film coating tablets or beads or for taste-masking. However, these dosage forms are used for immediate release administration of the active drug contained in the dosage form.
  • organic solvents in the preparation of polymer coatings is considered problematic as the formulations have inherent problems with regard to flammability, carcinogenicity, and safety in general. In addition, the use of organic solvents is disfavored due to environmental concerns.
  • a second sample consisted of phenylpropanolamine spheronized with microcrystalline cellulose in a 70:30 ratio, then coated with 15% ethyl cellulose applied from an aqueous dispersion. Samples from each batch were stored for up to four weeks under conditions of room temperature/ambient humidity; room temperature/high humidity (75% RH); 37° C./ambient humidity; and 37° C./high humidity. The data for the dissolution profiles indicated that the lag time and percent drug released at 8 hours were unstable at all conditions other than room temperature/ambient humidity conditions.
  • Aqueous polymeric dispersions have been used to produce stable controlled release dosage forms, but this has only been possible by other methods such/as incorporIation of the same into the matrix of the dosage form, rather than via the use of a coating of the aqueous polymeric dispersion to obtain retardant properties.
  • FIG. 1 compares the initial dissolution rate of the invention with that after 8 weeks of storage.
  • FIG. 2 compares the initial dissolution rate of a comparative example with that after 8 weeks of storage.
  • FIG. 3 compares the initial dissolution rate of a second comparative example with that after 8 weeks of storage.
  • FIG. 4 compares the initial dissolution rate of a third comparative example with that after 8 weeks of storage.
  • FIG. 5 demonstrates the stability of the dissolution rate of the invention under various storage conditions.
  • FIG. 6 compares the dissolution rate of the invention under various curing conditions with that of two comparative examples.
  • a solid dosage form which has a controlled release overcoat derived from an aqueous dispersion of a hydrophobic polymer which provides a substantially stable release pattern of a therapeutically active agent(s) contained therein.
  • the present invention further relates to the surprising discovery that when the coated formulation is exposed to certain elevated or "stressed" conditions of temperature and humidity for a certain amount of time, a desired endpoint may be attained whereat the release rate of the therapeutically active agent does not substantially change upon ageing under a wide range of temperature and/or humidity conditions.
  • This surprising discovery makes it possible to use aqueous dispersions of hydrophobic polymers for coating pharmaceutical dosage forms to produce stable controlled release pharmaceutical products.
  • the present invention is also related to a solid dosage form comprising a core comprising a therapeutically active agent and an overcoating derived from an aqueous dispersion of ethylcellulose in an amount sufficient to obtain a controlled release of the therapeutically active agent when the dosage form is exposed to aqueous solutions, e.g. gastric fluid.
  • the solid dosage form is cured after the overcoating is applied such that the release of the therapeutically active agent is substantially unchanged by exposure to temperature and/or humidity elevated above ambient conditions.
  • the present invention is also related to a stabilized controlled release solid dosage form for oral administration, comprising a plurality of inert pharmaceutically acceptable beads coated with a therapeutically active agent, and an ethylcellulose overcoat of a suitable thickness to obtain a controlled release of said therapeutically active agent when the solid dosage form is exposed to aqueous solutions, the ethylcellulose overcoat being derived from an aqueous dispersion of ethylcellulose with an effective amount of a suitable plasticizing agent.
  • the ethylcellulose coated beads are cured under stress conditions, i.e. at a temperature and relative humidity elevated to a suitable level above ambient conditions to attain a finished product which has a dissolution profile which is substantially unchanged by exposure to storage conditions of temperature and/or humidity elevated above ambient conditions.
  • stabilized and the phrase “substantially unchanged” with regard to the dissolution profile of the formulations of the present invention are defined for purposes of the present invention as meaning that the formulation reproducibly attains a dissolution profile which, even after exposure to accelerated storage conditions, falls within a certain range of drug release over time deemed to be within acceptable limits by one skilled in the art, e.g., the FDA or a corresponding foreign regulatory agency. Such an acceptable range is typically determined on a case-by-case basis, depending upon, among other things, the particular drug in question, the desired dosage regimen.
  • the present invention is further related to a stabilized solid controlled dosage form comprising a therapeutically active agent overcoated with an aqueous dispersion of ethylcellulose and cured at conditions of temperature and relative humidity greater than ambient conditions until a stabilized dissolution profile substantially unchanged by exposure to storage conditions of temperature and/or relative humidity elevated above ambient conditions is obtained.
  • the present invention is also related to a method for obtaining a stabilized controlled release formulation comprising a substrate coated with an aqueous dispersion of a hydrophobic polymer, comprising preparing an aqueous dispersion of ethylcellulose, preparing a substrate comprising a therapeutically active agent, overcoating the substrate with a sufficient amount of the aqueous dispersion of ethylcellulose to obtain a predetermined controlled release of the therapeutically active agent when the coated particles are exposed to aqueous solutions, and curing the coated substrate under stressed conditions by subjecting said coated particles to greater than ambient temperature and humidity and continuing the curing until an endpoint is reached at which the coated substrate attains a dissolution profile which is substantially unchanged by exposure to storage conditions of temperature and/or humidity elevated above ambient conditions.
  • the method further includes the step of determining the endpoint for a particular formulation by exposing the formulation to various stages of the above-mentioned curing and obtaining dissolution profiles for the formulation until the dissolution profiles of the formulation are substantially stabilized. The formulation is then modified, if necessary, to obtain a desired dissolution profile of the therapeutically active agent based on the end point.
  • Ethylcellulose which is a cellulose ether that is formed by the reaction of ethyl chloride with alkaline cellulose, is completely insoluble in water and gastrointestinal juices, and therefore to date has been considered not to be suitable by itself for tablet coating. It has, however, been commonly used in combination with hydroxypropyl methylcellulose and other film-formers to toughen or influence the dissolution rate of the film. Due to the solubility characteristics of ethylcellulose, this polymer has been mainly applied to the above-mentioned formulations from organic solutions.
  • film-coats are prepared by deposition of one or more film-forming polymers resulting in coats that usually represent no more than about 2-5% by weight of the final coated product.
  • the film-coating has been used in conjunction with the preparation of tablets, pills, capsules, granules, and powders.
  • the characteristics of the polymer used in the film-coating is governed by the structure, size and properties of its macromolecules.
  • Common film-formers used in pharmaceuticals as nonenteric materials include hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, ethylcellulose, and others.
  • the substrate comprising the therapeutically active agent In order to obtain a controlled release formulation, it is usually necessary to overcoat the substrate comprising the therapeutically active agent with a sufficient amount of the aqueous dispersion of ethylcellulose to obtain a weight gain level from about 5 to about 15 percent, although the overcoat may be lesser or greater depending upon the physical properties of the therapeutically active agent and the desired release rate, the inclusion of plasticizer in the acpeous dispersion of ethylcellulose and the manner of incorporation of the same, for example.
  • An example of a suitable controlled release formulation pursuant to the present invention will provide a dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C., is between 12.5 and 42.5% (by wt) therapeutically active agent released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt) released after 6 hours.
  • This example is, of course, not intended to be limiting in any manner whatsoever.
  • aqueous dispersions of hydrophobic polymers used as coatings in the present invention may be used in conjunction with tablets, spheroids (or beads), microspheres, seeds, pellets, ion-exchange resin beads, and other multi-particulate systems in order to obtain a desired controlled release of the therapeutically active agent.
  • Granules, spheroids, or pellets, and the like, prepared in accordance with the present invention can be presented in a capsule or in any other suitable dosage form.
  • ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize the ethylcellulose before using the same as a coating material.
  • Aquacoat® One commercially-available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
  • FMC states that Aquacoat® will undergo a rise in viscosity upon prolonged exposure to temperatures below 15° C. or above 35° C., and that viscosity can be reduced to less than 100 cps by applying shear (e.g., propeller type mixer).
  • shear e.g., propeller type mixer
  • FMC further states that a continuous film may be formed through a process known as gradual coalescence wherein the individual latex particles coalesce to form a continuous film of plasticized ethylcellulose polymer. After this period, the properties are said to remain constant. Higher coating temperatures, or a high temperature "curing" step is said by FMC to accelerate the process. If the coalescence process is not complete, FMC states that variability in release rates will result.
  • aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
  • Surelease® Colorcon, Inc., West Point, Pennsylvania, U.S.A.
  • the coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
  • the aqueous dispersion of ethylcellulose used in the present invention include an effective amount of a suitable plasticizing agent, as it has been found that the use of a plasticizer will further improve the physical properties of the film.
  • a suitable plasticizing agent as it has been found that the use of a plasticizer will further improve the physical properties of the film.
  • the plasticization of the ethylcellulose may be accomplished either by so-called “internal plasticization” and "external plasticization.”
  • Internal plasticization usually pertains directly to molecular modifications of the polymer during its manufacture, e.g., by copolymerization, such as altering and/or substituting functional groups, controlling the number of side chains, or controlling the length of the polymer. Such techniques are usually not performed by the formulator of the coating solution.
  • External plasticization involves the addition of a material to a film solution so that the requisite changes in film properties of the dry film can be achieved.
  • the suitability of a plasticizer depends on its affinity or solvating power for the polymer and its effectiveness at interfering with polymer-polymer attachments. Such activity imparts the desired flexibility by relieving molecular rigidity.
  • the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.
  • Tg glass transition temperature
  • the glass transition temperature is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer.
  • the polymer chain mobility is severely restricted.
  • the polymer will behave as a glass, being hard, non-pliable and rather brittle, properties which could be somewhat restrictive in film coating since the coated dosage form may be subjected to a certain amount of external stress.
  • suitable plasticizers include the ability of the plasticizer to act as a good "swelling agent" for the ethylcellulose, and the insolubility of the plasticizer in water.
  • plasticizers examples include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, and the like) may be used.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • the stabilized controlled release formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of ethylcellulose, altering the manner in which the plasticizer is added to the aqueous dispersion of ethylcellulose, by varying the amount of plasticizer relative to ethylcellulose, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, and the like.
  • the therapeutically active agents can be used in conjunction with the present invention.
  • the therapeutically active agents e.g. pharmaceutical agents
  • the therapeutically active agents include both water soluble and water insoluble drugs.
  • examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, and the like), non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), gastro-intestinals and anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedip
  • anti-spasmodics e.g. atropine, scopolamine
  • antidiabetics e.g., insulin
  • diuretics e.g., eltacrymic acid, bendrofluazide
  • anti-hypotensives e.g., propranolol, clonidine
  • bronchodilators e.g., albuterol
  • anti-inflammatory steroids e.g., hydrocortisone, triamcinolone, prednisone
  • antibiotics e.g., tetracycline
  • antihemorrhoidals hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine).
  • appetite suppressants such as phenylpropanolamine
  • the therapeutically active agent comprises hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing, and the like.
  • aqueous dispersion of ethylcellulose is used to coat inert pharmaceutical (nonpareil) beads such as nu pariel 18/20 beads
  • a plurality of the resultant stabilized solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid.
  • beads coated with a therapeutically active agent are prepared, e.g. by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Worster insert.
  • additional ingredients are also added prior to coating the beads in order to assist the hydromorphone binding to the beads, and/or to color the solution, and the like.
  • a product which includes hydroxypropyl methylcellulose (HPMC) and the like with or without colorant may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the beads.
  • the resultant coated substrate, in this example beads may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the ethylcellulose coating.
  • a suitable barrier agent is one which comprises hydroxypropyl methylcellulose.
  • any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.
  • the hydromorphone, HPMC protected (optional) beads may then be overcoated with an aqueous dispersion of ethylcellulose.
  • the aqueous dispersion of ethylcellulose preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
  • plasticizer e.g. triethyl citrate.
  • Pre-formulated aqueous dispersions of ethylcellulose such as Aquacoat® or Surelease®, may be used. If Surelease® is used, it is not necessary to separately add a plasticizer.
  • the coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction.
  • Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of ethylcellulose.
  • color can be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat®.
  • any suitable method of providing color to the formulations of the present invention may be used.
  • the plasticized aqueous dispersion of ethylcellulose may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art.
  • a sufficient amount of the aqueous dispersion of ethylcellulose to obtain a predetermined controlled release of said therapeutically active agent when said coated substrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, taking into account the physically characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, and the like.
  • a further overcoat of a film-former, such as Opadry® is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
  • the coated beads are cured in order to obtain a stabilized release rate of the therapeutically active agent.
  • Curing is traditionally carried out, if at all, via a forced-air oven at 60° C. for anywhere from 2-24 hours. This standard curing does not stabilize the dissolution profile of the formulation, as will be demonstrated by the examples set forth herein.
  • the curing step pursuant to the present invention is accomplished by subjecting the coated beads to "stressed conditions" by subjecting said coated substrate to a suitable level greater than normal, ambient (i.e., room) temperature and relative humidity and continuing the curing until an endpoint is reached at which the coated beads attain a dissolution profile which is substantially unaffected by further exposure to storage conditions of elevated temperature and/or humidity. More particularly, the coated substrates of the present invention should be cured at a temperature greater than the glass transition temperature of the coating solution (i.e., plasticizer ethylcellulose) and at a greater than ambient humidity (e.g., from about 60% to about 100% relative humidity).
  • the coating solution i.e., plasticizer ethylcellulose
  • the cured products of the present invention provide a release rate of the therapeutically active agent which is substantially unaffected during storage by elevations in temperature and humidity.
  • the stabilized product is obtained by subjecting the coated substrate to oven curing at elevated temperature/humidity levels for the required time period, the optimum values for temperature, humidity and time for the particular formulation being determined experimentally.
  • the stabilized product is obtained via an oven curing conducted at a temperature of about 60° C. and a relative humidity from about 60% to about 100% for a time period from about 48 to about 72 hours.
  • a temperature of about 60° C. and a relative humidity from about 60% to about 100% for a time period from about 48 to about 72 hours.
  • the tablet core e.g. the substrate
  • the active agent may comprise the active agent along with any pharmaceutically accepted inert pharmaceutical filler (diluent) material, including but not limited to sucrose, dextrose, lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures thereof and the like.
  • an effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may be added to the above-mentioned ingredients of the excipient prior to compression of the tablet core ingredients.
  • magnesium stearate in an amount of about 0.5-3% by weight of the solid dosage form.
  • Tablets overcoated with a sufficient amount of aqueous dispersions of ethylcellulose to achieve a controlled release formulation pursuant to the present invention may be prepared and cured in similar fashion as explained above with regard to the preparation of beads.
  • necessary curing conditions with regard to the particular elevated temperature, elevated humidity and time ranges necessary to obtain a stabilized product will depend upon the particular formulation.
  • Hydromorphone beads were prepared by dissolving hydromorphone HCl in water, adding Opadry® Y-5-1442, light pink (a product commercially available from Coloron, West Point, Pennsylvania, which contains hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and D&C Red No. 30 Aluminum Lake), 20% w/w, and mixing for about 1 hours, and then spraying onto nu pariel 18/20 beads using a Wurster insert. The resultant coated beads were then overcoated with Opadry® Y-5-1442 light pink (15% w/w). The resultant preparation had the formula set forth in Table 1 below:
  • hydromorphone, HPMC protected beads were then overcoated with 15% w/w Aquacoat® (including triethyl citrate), and then overcoated with Opadry® Light Pink 5% w/w after curing (see Table 2).
  • the beads cured at high humidity were dried in a fluid bed before the final overcoat.
  • Example 1 the coated beads were placed in a 30 cc amber glass vial and cured in an oven for 72 hours at 60° C./85% relative humidity.
  • Comparative Example 1A the coated beads were cured for 24 hours at 60° C. under dry conditions.
  • Comparative Example 1B the coated beads were cured for 72 hours at 60° C. under dry conditions.
  • Comparative Example 1C the coated beads were cured for 24 hours at 60° C. at 85% relative humidity.
  • the relative humidity in a water-filled desiccator in a 60° C. oven was determined as follows. First, about 500 grams of purified water is poured into a plastic desiccator and the metal guard inserted. A hygrometer/temperature indicator is placed on top of the guard and the desiccator covered and placed in the 60° C. oven for 24 hours. After 24 hours the relative humidity in the desiccator was 85% while the temperature was still 60° C. On placing the hygrometer alone in the 60° C. oven for 24 hours, the relative humidity was 9% at 60° C.
  • the dissolution tests were carried out via the USP Basket Method, 37° C., 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 900 ml at pH 7.5. In each instance, the dissolution was conducted by placing an open capsule containing the specified amount of cured beads (8mg hydromorphone HCl, 209 mg beads ⁇ 10%) into a vessel.
  • Example 1 It was observed that the dissolution of Example 1 did not change under these accelerated conditions, except that changes were seen with respect to the extreme conditions of 60° C./85% RH.
  • FIG. 1 is a graphical representation of the dissolution results obtained with Example 1, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80%RH.
  • FIG. 2 is a graphical representation of the dissolution profile of Comparative Example 1A, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80%RH.
  • FIG. 3 is a graphical representation of the dissolution profile of Comparative Example 1B, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80%RH.
  • FIG. 4 is a graphical representation of the dissolution profile of Comparative Example 1C, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80% RH.
  • Example 1 Comparing the results depicted in FIG. 1 (Example 1) with the results depicted in FIGS. 2-4 (the comparative examples), it is readly apparent that only in Example 1 were the initial and 8 week dissolution profiles substantially identical under storage conditions of 37° C./80%RH.
  • FIG. 5 is a graphical representation of the dissolution profiles of Example 1, comparing the initial dissolution profile with the dissolution profiles obtained after 8 weeks storage under various conditions (room temperature; 37° C./80%RH; and 60° C. dry). The dissolution profiles of Example 1 after 8 weeks under these various conditions is seen to be substantially identical.
  • FIG. 6 is a graphical representation of the initial dissolution profiles obtained after various curing conditions (curing of 2hrs at 60° C. dry (the prior art); 72hrs at 60° C./85%RH (Example 1); 24hrs at 60° C. dry (Comparative Example 1A); 60° C. dry (Comparative Example 1B); and 72hrs at 60° C. at 85% RH for 24 hrs (Comparative Example 1C)).
  • Example 2 hydromorphone HCl beads were prepared in accordance with Example 1 in order to determine if the stabilized initial dissolution achieved after curing at 60° C./85%RH could instead be achieved by a longer drying period without humidity. After coating with Aquacoat®, a further overcoat of Opadry® Y-5-1442, light pink is applied to the beads.
  • the coated product had the composition set forth in Table 12 below:
  • the Aquacoat® coated hydromorphone HCl beads were then cured in a 60° C. dry oven, and stored at 60° dry heat.
  • the cured beads were placed in open gelatin capsules containing the specified amount of cured beads (about 8mg hydromorphone HCl), and dissolution studies were then conducted in the manner set forth in Example 1 on three samples at the following time points: initial, 1 day, 2 days, 7 days, and 21 days in order to determine the stability of the dissolution profile. Dissolution studies were conducted as detailed above on the three samples. The mean results are set forth in Table 13 below:
  • Example 3 another attempt to stabilize Aquacoat® coated hydromorphone HCl beads using the premise that high temperature is not enough to insure complete coalescence of the ethylcellulose film. Normal time of mixing (and bonding) plasticizer and Aquacoat® is recommended by FMC to be 30 minutes. In Example 3, the contact time of the plasticizer (triethyl citrate) with the ethylcellulose polymer dispersion (Aquacoat®) was increased to 24 hours.
  • the coated beads were prepared in accordance with Example 1 and then placed in a 30 cc amber glass vial and cured in a 60° C. dry oven. Dissolution studies were then conducted on three samples at the following time points: 1 day, 2 days, 7 days and 11 days. Mean results are set forth in Table 14 below:
  • Hydromorphone beads were prepared by dissolving hydromorphone HCl in water, adding Opadry®, and mixing for about 1 hour, and then spraying onto nu pariel 18/20 beads using a Wurster insert. The resultant coated beads were then overcoated with Opadry® Y-5-1442 light pink (15% w/w). The beads were then overcoated with an aqueous dispersion of Aquacoat® to a 15% weight gain according to Table 15 below:
  • the beads were cured in a fluid bed for about 2 hours at 60° C., as sugested in the literature and as recommended by FMC, since it is above the Tg for Aquacoat® plasticized with triethyl citrate at 20% level of solids.
  • Examples 5-7 were manufactured at different levels of Aquacoat® load.
  • hydromorphone beads were made according to Example 1. Thereafter, overcoatings of 5% w/w, 10% w/w, and 15% w/w were applied to Examples 5-7 respectively, according to the formulas set forth in Tables 18-20:
  • Example 8 Hydromorphone beads overcoated with 10% of the Aquacoat® are prepared in accordance with Example 6.
  • the hydromorphone beads of Example 8 have the following formula set forth in Table 24 below:
  • Example 6 To test the effectiveness of curing at a lower relative humidity compared to Example 6, the above beads were cured for 72 hours at 60° C. at 60% relative humidity (rather than 85%RH). Similar initial results were obtained for Example 8 as compared to Example 6, thus indicating that the curing step can also be completed at a lower relative humidity. The results are set forth in Table 25 below:
  • Hydromorphone HC1 beads were prepared made by spraying a suspension of Hydromorphone HC1 and Opadry® Y-5-1442 light pink (20% w/w) onto nu-pariel 18/20 beads, in accordance with the method set forth in Example 1. These beads were then further coated with Opadry® Y-5-1442 light pink (15% w/w). These beads were then further coated with the Surelease® at a level of 10% weight gain.
  • the formula of the coated bead is set forth in Table 26:
  • Example 9 was cured at 60° C./85% RH for 3 days (72 hours), and then dried in a fluid bed dryer for 30 minutes at 60° C. to dry off the excess moisture. These beads were then overcoated with 5% Opadry light pink. Example 10 was left uncured.
  • a suspension of morphine sulphate and HPMC (Opadry® Clear Y-5-7095) was applied onto 18/20 mesh Nu-pariel beads in a fluid bed granulator with a Wurster insert, at 60° C.
  • a HPMC purple color suspension (Opadry® lavender YS-1-4729) was then applied as an overcoat at the same temperature.
  • the beads were then overcoated to a 5% weight gain with Aquacoat® and triethyl citrate as a plasticizer at 60° C. inlet.
  • the beads were then cured in an oven at 60° C./100% relative humidity for three days.
  • the beads were then dried in the fluid bed granulator at 60° C., and an overcoat of HPMC with a purple color was then applied using the Worster column.
  • Example 13 the applicability of another medicament, theophylline, having very different physical properties compared to hydromorphone is demonstrated.
  • Theophylline hydrous and colloidal silicona dioxide were first mixed together in a high shear mixer, then sieved using a Jet sieve to enhance flowability. Using a fluid bed granulator equipped with a rotor processor, sugar spheres were layered with the theophylline/colloidal silicon dioxide mixture using a PVP (C-30) solution. Layering was continued until an approximately 78% load was obtained.
  • Example 14 was prepared in order to attempt to improve the dissolution profile of the formulation via incorporation of this new curing step, and the coating was altered in order to increase the dissolution rate to 100% theophylline dissolved in 12 hours.
  • Example 14 was prepared as follows. Theophylline powder layered beads were made as described in Example 13 and were then overcoated with a plasticized Aquacoat® ECD 30 retardant, which, and for this example, included 10% HPMC (hydroxypropyl methyl cellulose). This was done so that the release of theophylline would be faster than Example 13. The inclusion of HPMC to speed up dissolution is known in the prior art. The retardant layer was also coated to a 6% weight gain in the Worster column of the fluid bed granulator.
  • HPMC hydroxypropyl methyl cellulose
  • hydrophobic polymer ethylcellulose
  • other hydrophobic polymers such as other cellulose derivatives
  • Such other hydrophobic polymers are considered to be within the scope of the appended claims.

Abstract

A stabilized solid controlled release dosage form having a coating derived from an aqueous dispersion of ethylcellulose is obtained by overcoating a substrate including a therapeutically active agent with an aqueous dispersion of ethylcellulose and then curing the coated substrate at a temperature and relative humidity elevated to a suitable level above ambient conditions until the coated dosage form attains a stabilized dissolution profile substantially unaffected by exposure to storage conditions of elevated temperature and/or elevated relative humidity.

Description

BACKGROUND THE INVENTION
It is the aim of all controlled release preparations to provide a longer duration of pharmacological response after the administration of the dosage form than is ordinarily experienced after the administration of an immediate release dosage form. Such extended periods of response provides for many inherent therapeutic benefits that are not achieved with short acting, immediate release products.
Controlled release formulations known in the art include specially coated beads or pellets, coated tablets and ion exchange resins, wherein the slow release of the active drug is brought about through selective breakdown of, or permeation through, the coating of the preparation or through formulation with a special matrix to affect the release of the drug.
An important aspect of all forms of controlled release dosage forms is related to the stability of the same. The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, pharmaceutical, and toxicological properties when stored, i.e., in a particular container and environment. Stability study requirements are covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as well as in New Drug Applications (NDAs) and Investigational New Drug Applications (INDs).
The ingredients used in sustained release dosage formulations often present special problems with regard to their physical stability during storage. For example, waxes which have been used in such formulations are known to undergo physical alterations on prolonged standing, thus precautions are taken to stabilize them at the time of manufacture or to prevent the change from occurring. Fats and waxy materials when used in purified states are known to crystallize in unstable forms, causing unpredictable variations in availability rates during stability testing at the time of manufacture and during later storage.
It is known that certain strategies can be undertaken to obtain stabilized controlled release formulations in many cases, such as insuring that the individual ingredients are in a stable form before they are incorporated into the product, and that processing does not change this condition, retarding the instability by including additional additives, and inducing the individual ingredients of the dosage form to reach a stable state before the product is finally completed.
It is also recognized that the moisture content of the product can also influence the stability of the product. Changes in the porosity and/or hydration level of a polymeric film, such as the ethyl celluloses, can alter the rate of water permeation and drug availability. Also, binders such as acacia are known to become less soluble when exposed to moisture and heat. Such problems have been handled by controls in the processing method and proper packaging of the product.
Hydrophobic polymers such as certain cellulose derivatives, zein, acrylic resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic acids have been used in the prior art to develop controlled release dosage forms. Methods of using these polymers to develop controlled release dosage forms such as tablets, capsules, suppositories, spheroids, beads or microspheres are to overcoat the individual dosage units with these hydrophobic polymers. It is known in the prior art that these hydrophobic coatings can be applied either from a solution, suspension or dry. Since most of these polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) and evaporating off the solvent.
Aqueous dispersions of hydrophobic polymers have been used in the prior art to coat pharmaceutical dosage forms for aesthetic reasons such as film coating tablets or beads or for taste-masking. However, these dosage forms are used for immediate release administration of the active drug contained in the dosage form.
The use of organic solvents in the preparation of polymer coatings is considered problematic as the formulations have inherent problems with regard to flammability, carcinogenicity, and safety in general. In addition, the use of organic solvents is disfavored due to environmental concerns.
Therefore, it is desirable to prepare a controlled release formulation prepared from an aqueous dispersion of a hydrophobic polymer. However, to date, attempts to prepare stable controlled release pharmaceutical formulations using aqueous dispersions of hydrophobic polymers have been unsuccessful due to stability problems. In particular, when coating these pharmaceutical forms using aqueous polymeric dispersions to obtain a desired release profile of the active drug(s) over several hours or longer, it is known in the art that the dissolution release profile changes on ageing. It is also known that this instability problem does not exist when the polymers are applied from organic solvent solution.
For example, Dressman, et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18 (1991), pp. 654-655, Controlled Release Society, Inc. reported on tests conducted which showed that phenylpropanolamine HCl pellets coated with an ethyl cellulose-based film are only stable at room temperature under ambient humidity conditions. In these experiments, phenylpropanolamine HCl was overlaid on sugar seeds to a 76% loading, and coated with 10% ethyl cellulose applied from an aqueous dispersion. A second sample consisted of phenylpropanolamine spheronized with microcrystalline cellulose in a 70:30 ratio, then coated with 15% ethyl cellulose applied from an aqueous dispersion. Samples from each batch were stored for up to four weeks under conditions of room temperature/ambient humidity; room temperature/high humidity (75% RH); 37° C./ambient humidity; and 37° C./high humidity. The data for the dissolution profiles indicated that the lag time and percent drug released at 8 hours were unstable at all conditions other than room temperature/ambient humidity conditions.
Although the authors considered the pellets to be unaffected by storage conditions, they concluded that the release mechanism from the phenylpropanolamine HCl pellets overcoated with ethyl cellulose-based films appear to depend upon the pellet composition, and that under high relative humidity storage, the rate of release may be effected, especially if the samples were stored at elevated temperature.
Munday, et al., Drug Devel. and Indus. Phar., 17 (15) 2135-2143 (1991) report that film coated theophylline mini-tablets film coated with ethyl cellulose with PEG (2:1), and ethyl cellulose with Eudragit L (2:1) proved to have impeded dissolution upon storage under stress conditions, the degree of slowdown of release being said to be directly proportional to temperature, while the effect of relative humidity (RH) appeared to be insignificant.
The authors concluded therein that the decreased rate of release was due to the slowing in the rate of molecular diffusion of the drug across the polymeric coating material, and suggested that the change was due to significant alterations in the permeability of the polymer which occurred during the experimental storage.
Aqueous polymeric dispersions have been used to produce stable controlled release dosage forms, but this has only been possible by other methods such/as incorporIation of the same into the matrix of the dosage form, rather than via the use of a coating of the aqueous polymeric dispersion to obtain retardant properties.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 compares the initial dissolution rate of the invention with that after 8 weeks of storage.
FIG. 2 compares the initial dissolution rate of a comparative example with that after 8 weeks of storage.
FIG. 3 compares the initial dissolution rate of a second comparative example with that after 8 weeks of storage.
FIG. 4 compares the initial dissolution rate of a third comparative example with that after 8 weeks of storage.
FIG. 5 demonstrates the stability of the dissolution rate of the invention under various storage conditions.
FIG. 6 compares the dissolution rate of the invention under various curing conditions with that of two comparative examples.
OBJECTS AND SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a controlled release dosage form for oral administration which comprises a coating of an aqueous dispersion of a hydrophobic polymer which is substantially stable despite exposure to elevated temperatures and/or elevated humidity levels during storage.
It is a further object of the present invention to provide a controlled release dosage form prepared with an overcoat of an aqueous dispersion of a hydrophobic polymer which is substantially stable under stress conditions, including even extended periods of high temperature and high humidity.
These objects and others have been accomplished by the present invention, which relates to a solid dosage form which has a controlled release overcoat derived from an aqueous dispersion of a hydrophobic polymer which provides a substantially stable release pattern of a therapeutically active agent(s) contained therein.
The present invention further relates to the surprising discovery that when the coated formulation is exposed to certain elevated or "stressed" conditions of temperature and humidity for a certain amount of time, a desired endpoint may be attained whereat the release rate of the therapeutically active agent does not substantially change upon ageing under a wide range of temperature and/or humidity conditions. This surprising discovery makes it possible to use aqueous dispersions of hydrophobic polymers for coating pharmaceutical dosage forms to produce stable controlled release pharmaceutical products.
The present invention is also related to a solid dosage form comprising a core comprising a therapeutically active agent and an overcoating derived from an aqueous dispersion of ethylcellulose in an amount sufficient to obtain a controlled release of the therapeutically active agent when the dosage form is exposed to aqueous solutions, e.g. gastric fluid. The solid dosage form is cured after the overcoating is applied such that the release of the therapeutically active agent is substantially unchanged by exposure to temperature and/or humidity elevated above ambient conditions.
The present invention is also related to a stabilized controlled release solid dosage form for oral administration, comprising a plurality of inert pharmaceutically acceptable beads coated with a therapeutically active agent, and an ethylcellulose overcoat of a suitable thickness to obtain a controlled release of said therapeutically active agent when the solid dosage form is exposed to aqueous solutions, the ethylcellulose overcoat being derived from an aqueous dispersion of ethylcellulose with an effective amount of a suitable plasticizing agent. The ethylcellulose coated beads are cured under stress conditions, i.e. at a temperature and relative humidity elevated to a suitable level above ambient conditions to attain a finished product which has a dissolution profile which is substantially unchanged by exposure to storage conditions of temperature and/or humidity elevated above ambient conditions.
The term "stabilized" and the phrase "substantially unchanged" with regard to the dissolution profile of the formulations of the present invention are defined for purposes of the present invention as meaning that the formulation reproducibly attains a dissolution profile which, even after exposure to accelerated storage conditions, falls within a certain range of drug release over time deemed to be within acceptable limits by one skilled in the art, e.g., the FDA or a corresponding foreign regulatory agency. Such an acceptable range is typically determined on a case-by-case basis, depending upon, among other things, the particular drug in question, the desired dosage regimen.
The present invention is further related to a stabilized solid controlled dosage form comprising a therapeutically active agent overcoated with an aqueous dispersion of ethylcellulose and cured at conditions of temperature and relative humidity greater than ambient conditions until a stabilized dissolution profile substantially unchanged by exposure to storage conditions of temperature and/or relative humidity elevated above ambient conditions is obtained.
The present invention is also related to a method for obtaining a stabilized controlled release formulation comprising a substrate coated with an aqueous dispersion of a hydrophobic polymer, comprising preparing an aqueous dispersion of ethylcellulose, preparing a substrate comprising a therapeutically active agent, overcoating the substrate with a sufficient amount of the aqueous dispersion of ethylcellulose to obtain a predetermined controlled release of the therapeutically active agent when the coated particles are exposed to aqueous solutions, and curing the coated substrate under stressed conditions by subjecting said coated particles to greater than ambient temperature and humidity and continuing the curing until an endpoint is reached at which the coated substrate attains a dissolution profile which is substantially unchanged by exposure to storage conditions of temperature and/or humidity elevated above ambient conditions.
In a further embodiment, the method further includes the step of determining the endpoint for a particular formulation by exposing the formulation to various stages of the above-mentioned curing and obtaining dissolution profiles for the formulation until the dissolution profiles of the formulation are substantially stabilized. The formulation is then modified, if necessary, to obtain a desired dissolution profile of the therapeutically active agent based on the end point.
DETAILED DESCRIPTION
Ethylcellulose, which is a cellulose ether that is formed by the reaction of ethyl chloride with alkaline cellulose, is completely insoluble in water and gastrointestinal juices, and therefore to date has been considered not to be suitable by itself for tablet coating. It has, however, been commonly used in combination with hydroxypropyl methylcellulose and other film-formers to toughen or influence the dissolution rate of the film. Due to the solubility characteristics of ethylcellulose, this polymer has been mainly applied to the above-mentioned formulations from organic solutions.
Many polymers have been investigated for use in film-coating. Most film-coats are prepared by deposition of one or more film-forming polymers resulting in coats that usually represent no more than about 2-5% by weight of the final coated product. The film-coating has been used in conjunction with the preparation of tablets, pills, capsules, granules, and powders. The characteristics of the polymer used in the film-coating is governed by the structure, size and properties of its macromolecules. Common film-formers used in pharmaceuticals as nonenteric materials include hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, ethylcellulose, and others.
In order to obtain a controlled release formulation, it is usually necessary to overcoat the substrate comprising the therapeutically active agent with a sufficient amount of the aqueous dispersion of ethylcellulose to obtain a weight gain level from about 5 to about 15 percent, although the overcoat may be lesser or greater depending upon the physical properties of the therapeutically active agent and the desired release rate, the inclusion of plasticizer in the acpeous dispersion of ethylcellulose and the manner of incorporation of the same, for example.
An example of a suitable controlled release formulation pursuant to the present invention will provide a dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C., is between 12.5 and 42.5% (by wt) therapeutically active agent released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt) released after 6 hours. This example is, of course, not intended to be limiting in any manner whatsoever.
The aqueous dispersions of hydrophobic polymers used as coatings in the present invention may be used in conjunction with tablets, spheroids (or beads), microspheres, seeds, pellets, ion-exchange resin beads, and other multi-particulate systems in order to obtain a desired controlled release of the therapeutically active agent. Granules, spheroids, or pellets, and the like, prepared in accordance with the present invention can be presented in a capsule or in any other suitable dosage form.
Because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize the ethylcellulose before using the same as a coating material.
One commercially-available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
With respect to handling and storage conditions, FMC states that Aquacoat® will undergo a rise in viscosity upon prolonged exposure to temperatures below 15° C. or above 35° C., and that viscosity can be reduced to less than 100 cps by applying shear (e.g., propeller type mixer). FMC further states that a continuous film may be formed through a process known as gradual coalescence wherein the individual latex particles coalesce to form a continuous film of plasticized ethylcellulose polymer. After this period, the properties are said to remain constant. Higher coating temperatures, or a high temperature "curing" step is said by FMC to accelerate the process. If the coalescence process is not complete, FMC states that variability in release rates will result.
However, as will be demonstrated by the examples provided herein, it has been found that curing the film coating simply by utilizing a higher coating temperature or a high temperature curing step will not effectively stabilize the dissolution profile of the product upon storing.
Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
The coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
It is preferred that the aqueous dispersion of ethylcellulose used in the present invention include an effective amount of a suitable plasticizing agent, as it has been found that the use of a plasticizer will further improve the physical properties of the film. The plasticization of the ethylcellulose may be accomplished either by so-called "internal plasticization" and "external plasticization."
Internal plasticization usually pertains directly to molecular modifications of the polymer during its manufacture, e.g., by copolymerization, such as altering and/or substituting functional groups, controlling the number of side chains, or controlling the length of the polymer. Such techniques are usually not performed by the formulator of the coating solution.
External plasticization involves the addition of a material to a film solution so that the requisite changes in film properties of the dry film can be achieved.
The suitability of a plasticizer depends on its affinity or solvating power for the polymer and its effectiveness at interfering with polymer-polymer attachments. Such activity imparts the desired flexibility by relieving molecular rigidity. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.
An important parameter in the determination of a suitable plasticizer for a polymer is related to the glass transition temperature (Tg) of the polymer. The glass transition temperature is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer.
Below the Tg, the polymer chain mobility is severely restricted. Thus, for a given polymer, if its Tg is above room temperature, the polymer will behave as a glass, being hard, non-pliable and rather brittle, properties which could be somewhat restrictive in film coating since the coated dosage form may be subjected to a certain amount of external stress.
Incorporation of suitable plasticizers into the polymer matrix effectively reduces the Tg, so that under ambient conditions the films are softer, more pliable and often stronger, and thus better able to resist mechanical stress.
Other aspects of suitable plasticizers include the ability of the plasticizer to act as a good "swelling agent" for the ethylcellulose, and the insolubility of the plasticizer in water.
Examples of suitable plasticizers include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, and the like) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
The stabilized controlled release formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of ethylcellulose, altering the manner in which the plasticizer is added to the aqueous dispersion of ethylcellulose, by varying the amount of plasticizer relative to ethylcellulose, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, and the like.
A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e.g. pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, and the like), non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), gastro-intestinals and anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g. theophylline), anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., eltacrymic acid, bendrofluazide), anti-hypotensives (e.g., propranolol, clonidine), bronchodilators (e.g., albuterol), anti-inflammatory steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive.
In certain preferred embodiments, the therapeutically active agent comprises hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing, and the like.
When the aqueous dispersion of ethylcellulose is used to coat inert pharmaceutical (nonpareil) beads such as nu pariel 18/20 beads, a plurality of the resultant stabilized solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid. In this embodiment, beads coated with a therapeutically active agent are prepared, e.g. by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Worster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the hydromorphone binding to the beads, and/or to color the solution, and the like. For example, a product which includes hydroxypropyl methylcellulose (HPMC) and the like with or without colorant may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the beads. The resultant coated substrate, in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the ethylcellulose coating. An example of a suitable barrier agent is one which comprises hydroxypropyl methylcellulose. However, any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.
The hydromorphone, HPMC protected (optional) beads may then be overcoated with an aqueous dispersion of ethylcellulose. The aqueous dispersion of ethylcellulose preferably further includes an effective amount of plasticizer, e.g. triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat® or Surelease®, may be used. If Surelease® is used, it is not necessary to separately add a plasticizer.
The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of ethylcellulose. For example, color can be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat®. Alternatively, any suitable method of providing color to the formulations of the present invention may be used.
The plasticized aqueous dispersion of ethylcellulose may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art. A sufficient amount of the aqueous dispersion of ethylcellulose to obtain a predetermined controlled release of said therapeutically active agent when said coated substrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, taking into account the physically characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, and the like. After coating with Aquacoat®, a further overcoat of a film-former, such as Opadry®, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
Next, the coated beads are cured in order to obtain a stabilized release rate of the therapeutically active agent. Curing is traditionally carried out, if at all, via a forced-air oven at 60° C. for anywhere from 2-24 hours. This standard curing does not stabilize the dissolution profile of the formulation, as will be demonstrated by the examples set forth herein.
The curing step pursuant to the present invention is accomplished by subjecting the coated beads to "stressed conditions" by subjecting said coated substrate to a suitable level greater than normal, ambient (i.e., room) temperature and relative humidity and continuing the curing until an endpoint is reached at which the coated beads attain a dissolution profile which is substantially unaffected by further exposure to storage conditions of elevated temperature and/or humidity. More particularly, the coated substrates of the present invention should be cured at a temperature greater than the glass transition temperature of the coating solution (i.e., plasticizer ethylcellulose) and at a greater than ambient humidity (e.g., from about 60% to about 100% relative humidity).
One possible mechanism for the change in the dissolution profile of prior art products cured by the standard methods, i.e. curing for 2 hours or more at 60° C. dry heat, is that these products continue to cure during storage, and may never reach a stabilized end-point at which the product provides a substantially constant dissolution profile. In contrast, the cured products of the present invention provide a release rate of the therapeutically active agent which is substantially unaffected during storage by elevations in temperature and humidity.
In preferred embodiments of the present invention, the stabilized product is obtained by subjecting the coated substrate to oven curing at elevated temperature/humidity levels for the required time period, the optimum values for temperature, humidity and time for the particular formulation being determined experimentally.
In certain embodiments of the present invention, the stabilized product is obtained via an oven curing conducted at a temperature of about 60° C. and a relative humidity from about 60% to about 100% for a time period from about 48 to about 72 hours. This is the case for the hydromorphone beads described in the examples provided below. However, one skilled in the art will recognize that necessary curing conditions may be changed somewhat, and may in fact be broader than the above-mentioned temperature, humidity and time ranges, depending upon the particular formulation, in order to obtain a stabilized product.
When the controlled release coating of the present invention is to be applied to tablets, the tablet core (e.g. the substrate) may comprise the active agent along with any pharmaceutically accepted inert pharmaceutical filler (diluent) material, including but not limited to sucrose, dextrose, lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures thereof and the like. Also, an effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may be added to the above-mentioned ingredients of the excipient prior to compression of the tablet core ingredients. Most preferred is magnesium stearate in an amount of about 0.5-3% by weight of the solid dosage form.
Tablets overcoated with a sufficient amount of aqueous dispersions of ethylcellulose to achieve a controlled release formulation pursuant to the present invention may be prepared and cured in similar fashion as explained above with regard to the preparation of beads. One skilled in the art will recognize that necessary curing conditions with regard to the particular elevated temperature, elevated humidity and time ranges necessary to obtain a stabilized product, will depend upon the particular formulation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever. In the following Tables which report the results of dissolution tests, the underlined numerals specify hours and the columns beneath them specify percent dissolved.
EXAMPLE 1
Hydromorphone beads were prepared by dissolving hydromorphone HCl in water, adding Opadry® Y-5-1442, light pink (a product commercially available from Coloron, West Point, Pennsylvania, which contains hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and D&C Red No. 30 Aluminum Lake), 20% w/w, and mixing for about 1 hours, and then spraying onto nu pariel 18/20 beads using a Wurster insert. The resultant coated beads were then overcoated with Opadry® Y-5-1442 light pink (15% w/w). The resultant preparation had the formula set forth in Table 1 below:
              TABLE 1                                                     
______________________________________                                    
Ingredient           Percent  Amt/Unit                                    
______________________________________                                    
Hydromorphone HCl    4.75%    4 mg                                        
Nu Pariel 18/20      87.9%    74 mg                                       
Opadry ® Lt. Pink Y-5-1442                                            
                     2.4%     2 mg                                        
Opadry ® Lt. Pink Y-5-1442 (overcoat)                                 
                     5.0%     4.2 mg                                      
                     100.0%   84.2 mg                                     
______________________________________
The hydromorphone, HPMC protected beads were then overcoated with 15% w/w Aquacoat® (including triethyl citrate), and then overcoated with Opadry® Light Pink 5% w/w after curing (see Table 2). The beads cured at high humidity were dried in a fluid bed before the final overcoat.
              TABLE 2                                                     
______________________________________                                    
Composition After Coating                                                 
Ingredient        Percent                                                 
______________________________________                                    
Hydromorphone beads                                                       
                  80.57%                                                  
Aquacoat ® ECD 30                                                     
                  12.06%                                                  
Triethyl citrate   2.39%                                                  
Opadry ® Lt. Pink                                                     
                   4.98%                                                  
Y-5-1442 (Overcoat)                                                       
                  100.0%                                                  
______________________________________
The product was then divided into four portions. In Example 1, the coated beads were placed in a 30 cc amber glass vial and cured in an oven for 72 hours at 60° C./85% relative humidity. In Comparative Example 1A, the coated beads were cured for 24 hours at 60° C. under dry conditions. In Comparative Example 1B, the coated beads were cured for 72 hours at 60° C. under dry conditions. In Comparative Example 1C, the coated beads were cured for 24 hours at 60° C. at 85% relative humidity.
All products cured at the four above-mentioned different conditions were then tested for stability under the following conditions: Room Temperature; 37° C. dry; 37° C./80% Relative Humidity (RH); 50° C. dry; 60° C. dry; and 60° C./85% RH.
The relative humidity in a water-filled desiccator in a 60° C. oven was determined as follows. First, about 500 grams of purified water is poured into a plastic desiccator and the metal guard inserted. A hygrometer/temperature indicator is placed on top of the guard and the desiccator covered and placed in the 60° C. oven for 24 hours. After 24 hours the relative humidity in the desiccator was 85% while the temperature was still 60° C. On placing the hygrometer alone in the 60° C. oven for 24 hours, the relative humidity was 9% at 60° C.
The dissolution tests were carried out via the USP Basket Method, 37° C., 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 900 ml at pH 7.5. In each instance, the dissolution was conducted by placing an open capsule containing the specified amount of cured beads (8mg hydromorphone HCl, 209 mg beads±10%) into a vessel.
It was observed that the dissolution of Example 1 did not change under these accelerated conditions, except that changes were seen with respect to the extreme conditions of 60° C./85% RH. The results for Example 1 are set forth in Tables 3-8 below, :
              TABLE 3                                                     
______________________________________                                    
ROOM TEMPERATURE                                                          
      Hydromor-                                                           
Time  phone HCl  Dissolution                                              
(wks) (Amount)   1     2    4    8    12   18   24                        
______________________________________                                    
Initial                                                                   
      8.14 mg    0     4.6  29.5 52.6 64.7 76.6 82.8                      
1     7.95 mg    0     5.1  30.3 55.0 67.4 79.8 88.9                      
4     7.80 mg    1.3   8.2  33.5 57.4 70.0 82.8 90.9                      
8     7.78 mg    0.7   6.0  30.5 54.0 66.4 78.0 88.2                      
______________________________________                                    

              TABLE 4                                                     
______________________________________                                    
37° C. DRY                                                         
      Hydromor-                                                           
Time  phone HCl  Dissolution                                              
(wks) (Amount)   1     2    4    8    12   18   24                        
______________________________________                                    
Initial                                                                   
      8.14 mg    0     4.6  29.5 52.6 64.7 76.6 82.8                      
1     7.96 mg    0     6.0  30.8 55.3 68.0 81.6 89.7                      
4     7.91 mg    2     8.1  33.2 56.6 70.2 82.0 91.3                      
8     7.73 mg    1     5.8  31.3 57.5 64.6 82.7 91.6                      
______________________________________                                    

              TABLE 5                                                     
______________________________________                                    
37° C./80% RH                                                      
      Hydromor-                                                           
Time  phone HCl  Dissolution                                              
(wks) (Amount)   1     2    4    8    12   18   24                        
______________________________________                                    
Initial                                                                   
      8.19 mg    0     4.6  29.5 52.6 64.7 76.6 82.8                      
1     7.85 mg    0     5.6  31.0 55.1 68.5 80.3 89.1                      
4     8.16 mg    2.4   7.6  32.3 52.8 64.4 75.4 82.7                      
8     8.22 mg    2.9   7.9  33.5 53.3 64.5 73.6 81.3                      
______________________________________                                    

              TABLE 6                                                     
______________________________________                                    
50° C. (dry)                                                       
      Hydromor-                                                           
Time  phone HCl  Dissolution                                              
(wks) (Amount)   1     2    4    8    12   18   24                        
______________________________________                                    
Initial                                                                   
      8.14 mg    0     4.6  29.5 52.6 64.7 76.6 82.8                      
1     8.14 mg    0     6.3  32.7 56.3 68.3 80.8 89                        
4     7.81 mg    2.3   10   37.0 59.6 72.0 84.5 92                        
8     7.74 mg    2     10.4 35.8 59.2 71.3 82.3 90.5                      
______________________________________                                    

              TABLE 7                                                     
______________________________________                                    
60° C. (dry)                                                       
      Hydromor-                                                           
Time  phone HCl  Dissolution                                              
(wks) (Amount)   1     2    4    8    12   18   24                        
______________________________________                                    
Initial                                                                   
      8.14 mg    0     4.6  29.5 52.6 64.7 76.6 82.8                      
1     8.13 mg    0     6.7  34.6 57.8 70.3 82.1 90.5                      
4     8.30 mg    2.7   10.6 36.6 56.8 68.7 80.4 85.6                      
8     7.94 mg    3.6   11.9 37.4 58.4 71.1 80.6 89.3                      
______________________________________                                    

              TABLE 8                                                     
______________________________________                                    
60° C./100% RH                                                     
      Hydromor-                                                           
Time  phone HCl  Dissolution                                              
(wks) (Amount)   1     2    4    8    12   18   24                        
______________________________________                                    
Initial                                                                   
      8.14 mg   0       4.6 29.5 52.6 64.7 76.6 82.8                      
1     7.26 mg   6.1     9.9 23.4 42.4 53.3 63.1 72.5                      
4     6.64 mg   19     23.7 32.5 41.4 46.7 53.0 51.7                      
8     5.38 mg   25.1   28.4 33.2 40.0 44.1 47.7 52.0                      
______________________________________
In contrast, the dissolution profiles of Comparative Examples 1A, 1B and 1C continued to slow down (e.g., cure) at all accelerated conditions. The results are set forth in Tables 9, 10 and 11, respectively.
                                  TABLE 9                                 
__________________________________________________________________________
Comparative Example 1A                                                    
         Hydromorphone                                                    
Conditions/                                                               
         HCl      Dissolution                                             
Time     (Amount) 1  2  4  8  12 18 24                                    
__________________________________________________________________________
Initial  9.03 mg  17.8                                                    
                     43.6                                                 
                        63.6                                              
                           78.8                                           
                              86.7                                        
                                 94.7                                     
                                    94.2                                  
Room Temp.                                                                
         8.79 mg  18.4                                                    
                     35.9                                                 
                        58.2                                              
                           76.3                                           
                              88.7                                        
                                 97 *                                     
8 wks                                                                     
37° C. (dry)                                                       
         8.50 mg  14 36.5                                                 
                        59.1                                              
                           81.1                                           
                              91.4                                        
                                 99.4                                     
                                    *                                     
8 wks                                                                     
37° C./80% RH                                                      
         8.15 mg   6.6                                                    
                     23.6                                                 
                        41.2                                              
                           60.7                                           
                              72.3                                        
                                 83.1                                     
                                    *                                     
8 wks                                                                     
50° C. (dry)                                                       
         8.45 mg  17.3                                                    
                     36 56.1                                              
                           78.1                                           
                              89.1                                        
                                 97.1                                     
                                    102.6                                 
8 wks                                                                     
60° C. (dry)                                                       
         8.65 mg   7.3                                                    
                     28.5                                                 
                        48.9                                              
                           64.4                                           
                              82 92.3                                     
                                    99.1                                  
8 wks                                                                     
60° C./100% RH                                                     
         5.81 mg  17.5                                                    
                     22.6                                                 
                        28.8                                              
                           36.5                                           
                              41.7                                        
                                 46.5                                     
                                    50.3                                  
8 wks                                                                     
__________________________________________________________________________

                                  TABLE 10                                
__________________________________________________________________________
Comparative Example 1B                                                    
         Hydromorphone                                                    
Conditions/                                                               
         HCl      Dissolution                                             
Time     (Amount) 1  2  4  8  12 18 24                                    
__________________________________________________________________________
Initial  8.82 mg  4.7                                                     
                     35.5                                                 
                        58.3                                              
                           75.6                                           
                              87.3                                        
                                 96.0                                     
                                     98.2                                 
Room Temp.                                                                
         8.29 mg  8.7                                                     
                     34.6                                                 
                        59.3                                              
                           80.8                                           
                              92.1                                        
                                 99.2                                     
                                    105.7                                 
8 wks                                                                     
37° C. (dry)                                                       
         8.34 mg  8.3                                                     
                     36.1                                                 
                        55.9                                              
                           77.4                                           
                              87.3                                        
                                 97.8                                     
                                    103.1                                 
8 wks                                                                     
37° C./80% RH                                                      
         8.86 mg  4.9                                                     
                     25.4                                                 
                        43.6                                              
                           61.7                                           
                              70 80  87.2                                 
8 wks                                                                     
50° C. (dry)                                                       
         8.71 mg  10.8                                                    
                     35.4                                                 
                        55.9                                              
                           77.2                                           
                              88.9                                        
                                 99.5                                     
                                    103.2                                 
8 wks                                                                     
60° C. (dry)                                                       
         8.30 mg  5.3                                                     
                     32 54.1                                              
                           76.6                                           
                              87.2                                        
                                 99.8                                     
                                    105.5                                 
8 wks                                                                     
60° C./100% RH                                                     
         6.22 mg  16.3                                                    
                     21.2                                                 
                        27.4                                              
                           35.9                                           
                              40.5                                        
                                 46.2                                     
                                     49.4                                 
8 wks                                                                     
__________________________________________________________________________

                                  TABLE 11                                
__________________________________________________________________________
Comparative Example 1C                                                    
         Hydromorphone                                                    
Conditions/                                                               
         HCl      Dissolution                                             
Time     (Amount) 1  2  4  8  12 18 24                                    
__________________________________________________________________________
Initial  8.71 mg  0.7                                                     
                     15.3                                                 
                        41.9                                              
                           60.7                                           
                              71.2                                        
                                 82.4                                     
                                    86.7                                  
Room Temp.                                                                
         8.40 mg  1  14.2                                                 
                        39.8                                              
                           58.8                                           
                              69.1                                        
                                 79.1                                     
                                    87.2                                  
8 wks                                                                     
37° C. (dry)                                                       
         8.84 mg  2.7                                                     
                     14.5                                                 
                        40.5                                              
                           60.4                                           
                              71 81.3                                     
                                    89.8                                  
8 wks                                                                     
37° C./80% RH                                                      
         8.78 mg  2.5                                                     
                     12.4                                                 
                        37.8                                              
                           54.6                                           
                              63.8                                        
                                 73.3                                     
                                    *                                     
8 wks                                                                     
50° C. (dry)                                                       
         8.71 mg  3.2                                                     
                     17.5                                                 
                        42.3                                              
                           61.1                                           
                              70.8                                        
                                 81 87.9                                  
8 wks                                                                     
60° C. (dry)                                                       
         8.57 mg  2.9                                                     
                     18.2                                                 
                        43.4                                              
                           62.5                                           
                              73.6                                        
                                 84.3                                     
                                    *                                     
8 wks                                                                     
60° C./100% RH                                                     
         6.10 mg  15.7                                                    
                     20.3                                                 
                        26.4                                              
                           33.8                                           
                              38.3                                        
                                 43.1                                     
                                    46.7                                  
8 wks                                                                     
__________________________________________________________________________
FIG. 1 is a graphical representation of the dissolution results obtained with Example 1, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80%RH.
FIG. 2 is a graphical representation of the dissolution profile of Comparative Example 1A, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80%RH.
FIG. 3 is a graphical representation of the dissolution profile of Comparative Example 1B, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80%RH.
FIG. 4 is a graphical representation of the dissolution profile of Comparative Example 1C, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37° C./80% RH.
Comparing the results depicted in FIG. 1 (Example 1) with the results depicted in FIGS. 2-4 (the comparative examples), it is readly apparent that only in Example 1 were the initial and 8 week dissolution profiles substantially identical under storage conditions of 37° C./80%RH.
FIG. 5 is a graphical representation of the dissolution profiles of Example 1, comparing the initial dissolution profile with the dissolution profiles obtained after 8 weeks storage under various conditions (room temperature; 37° C./80%RH; and 60° C. dry). The dissolution profiles of Example 1 after 8 weeks under these various conditions is seen to be substantially identical.
Finally, FIG. 6 is a graphical representation of the initial dissolution profiles obtained after various curing conditions (curing of 2hrs at 60° C. dry (the prior art); 72hrs at 60° C./85%RH (Example 1); 24hrs at 60° C. dry (Comparative Example 1A); 60° C. dry (Comparative Example 1B); and 72hrs at 60° C. at 85% RH for 24 hrs (Comparative Example 1C)).
EXAMPLE 2 - Curing at 60° C. Dry Heat - Longer Drying
In Example 2, hydromorphone HCl beads were prepared in accordance with Example 1 in order to determine if the stabilized initial dissolution achieved after curing at 60° C./85%RH could instead be achieved by a longer drying period without humidity. After coating with Aquacoat®, a further overcoat of Opadry® Y-5-1442, light pink is applied to the beads. The coated product had the composition set forth in Table 12 below:
              TABLE 12                                                    
______________________________________                                    
Composition After Coating                                                 
Ingredient         Percent    Amt/Unit                                    
______________________________________                                    
Hydromorphone beads                                                       
                   80.57%     84.2 mg                                     
Aquacoat ® ECD 30                                                     
                   12.06%     12.6 mg                                     
Triethyl citrate    2.39%      2.5 mg                                     
Opadry ® Lt. Pink (Overcoat)                                          
                    4.98%      5.2 mg                                     
                   100.0%     99.3 mg                                     
______________________________________
The Aquacoat® coated hydromorphone HCl beads were then cured in a 60° C. dry oven, and stored at 60° dry heat. The cured beads were placed in open gelatin capsules containing the specified amount of cured beads (about 8mg hydromorphone HCl), and dissolution studies were then conducted in the manner set forth in Example 1 on three samples at the following time points: initial, 1 day, 2 days, 7 days, and 21 days in order to determine the stability of the dissolution profile. Dissolution studies were conducted as detailed above on the three samples. The mean results are set forth in Table 13 below:
              TABLE 13                                                    
______________________________________                                    
Dissolution (Time)                                                        
Time  Wt                                                                  
(Days)                                                                    
      (mg)   1 hr   2 hr 4 hr 8 hr 12 hrs                                 
                                         18 hrs                           
                                               24 hrs                     
______________________________________                                    
Initial                                                                   
      196.7  15.6   43.8 68.7 89.9 101.0 109.2 113.8                      
1     196.3   3.7   37.5 63.5 84.9 97.5  107.2 112.3                      
2     196.3   4.8   37.0 62.9 84.8 95.1  104.7 111.8                      
7     197.3  13.5   37.8 63.3 84.9 98.8  108.6 115.9                      
21    197.3  17.4   36.5 58.4 77.9 88.9   98.2 103.1                      
______________________________________
From the results set forth in Table 13 above, it is apparent that a profound slowdown in release rate of the samples of Example 2did not occur, as compared with the high temperature/high humidity condition of Example 1. In other words, an endpoint was not reached at which the dissolution profile matches the base level of Example 1. This profound slow down is apparent when comparing, e.g. the initial dissolution of the drug in Tables 3-8 (Example 1) versus the initial dissolution of the drug in Table 13 (Example 2) (e.g., 0% vs. 15.6% release after one hour; 4.6% vs. 43.8% releases after two hours; 29.5% vs. 68.7% release after four hours). The release rate of drug for Example 2, however, would eventually slow down to match the dissolution rate of Example1 after being exposed to accelerated storage conditions.
EXAMPLE 3 - Increased mixing Time
In Example 3, another attempt to stabilize Aquacoat® coated hydromorphone HCl beads using the premise that high temperature is not enough to insure complete coalescence of the ethylcellulose film. Normal time of mixing (and bonding) plasticizer and Aquacoat® is recommended by FMC to be 30 minutes. In Example 3, the contact time of the plasticizer (triethyl citrate) with the ethylcellulose polymer dispersion (Aquacoat®) was increased to 24 hours.
The coated beads were prepared in accordance with Example 1 and then placed in a 30 cc amber glass vial and cured in a 60° C. dry oven. Dissolution studies were then conducted on three samples at the following time points: 1 day, 2 days, 7 days and 11 days. Mean results are set forth in Table 14 below:
              TABLE 14                                                    
______________________________________                                    
Dissolution (Time)                                                        
Time  Wt                                                                  
(Days)                                                                    
      (mg)   1 hr   2 hr 4 hr 8 hr 12 hrs                                 
                                         18 hrs                           
                                               24 hrs                     
______________________________________                                    
1     210.7  27.7   53.3 77.3 95.7 103.4 108.2 110.4                      
2     209.7  25.9   50.3 74.3 94.2 101.9 106.4 110.2                      
7     209.7  24.8   48.3 73.1 95.2 102.7 108.5 112.6                      
11    210.3  24.0   45.4 70.5 94.9 103.9 113.3 115.9                      
______________________________________
From the results set forth in Table 14 above, it is apparent that a profound slow down in release rate of the samples of Example 3 did not occur, as compared with the release rates both initially and under the high temperature/high humidity conditions of Example 1. In other words, an endpoint was not reached at which the dissolution profile gets down to the base level of Example 1 . This profound slowdown in release rate is apparent when comparing e.g., the initial dissolution of the drug in Tables 3-8 (Example 1) versus the dissolution of the drug after one day storage (e.g., 0% vs. 27.7% release after one hour; 4.6% vs. 53.3% release after two hours; 29.5% vs. 77.3% release after four hours.
EXAMPLE 4 - Recommended Curing (Prior Art)
Hydromorphone beads were prepared by dissolving hydromorphone HCl in water, adding Opadry®, and mixing for about 1 hour, and then spraying onto nu pariel 18/20 beads using a Wurster insert. The resultant coated beads were then overcoated with Opadry® Y-5-1442 light pink (15% w/w). The beads were then overcoated with an aqueous dispersion of Aquacoat® to a 15% weight gain according to Table 15 below:
              TABLE 15                                                    
______________________________________                                    
Ingredient      Percent (wt)                                              
                           Amt/Unit                                       
______________________________________                                    
Hydromorphone beads                                                       
                84.7       80 mg                                          
Aquacoat ® CD 30                                                      
                12.7       12 mg                                          
Citroflex ® 2A                                                        
                 2.5       2.4 mg                                         
(Triethylcitrate)                                                         
                99.9       94.4 mg                                        
______________________________________
After the resin was applied to the beads, the beads were cured in a fluid bed for about 2 hours at 60° C., as sugested in the literature and as recommended by FMC, since it is above the Tg for Aquacoat® plasticized with triethyl citrate at 20% level of solids.
The cured beads were then stored at room temperature, with dissolution studies being conducted initially and at 3 months. Samples were also stored at 37° C./80% RH. The mean results are provided in Table 16:
              TABLE 16                                                    
______________________________________                                    
      Mean    1      2    4    8    12   18    24                         
Time  wt      hr     hr   hr   hr   hrs  hrs   hrs                        
______________________________________                                    
Initial                                                                   
      283.2   30.4   44   70.2 89.1 97.0 101.3 102.1                      
3 mos 282.3   36.2   57.8 76.9 89.0 93.4 96.6  98.5                       
37° C./80% RH                                                      
1 mo  288.4   0.5    26.7 50.5 69.6 80.7 90.7  97.0                       
2 mos 287.3   0.6    25.1 50.7 70.3 81.6 92.2  98.8                       
3 mos 293.7   1.2    23.7 48.6 65.6 74.5 80.2  83.5                       
______________________________________
From the results provided in Table 16 above, it can be seen that the dissolution profile of the samples stored at room temperature were acceptable. However, the dissolution of the samples slowed dramatically when stored at 37° C./80% RH.
Samples from the batch of Example 4 were repackaged, stored and thereafter subjected to heat uner dry conditions at 37° C. and moisture (37° C./80% RH). The dissolution results are provided in Table 17 below:
              TABLE 17                                                    
______________________________________                                    
      Mean    1      2    4    8    12   18    24                         
Time  wt      hr     hr   hr   hr   hrs  hrs   hrs                        
______________________________________                                    
Initial                                                                   
      283.2   30.4   49.0 70.3 89.1 97.0 101.3 102.1                      
37° Dry                                                            
2 wks 283.2   25.0   44.4 65.0 84.5 92.9 100.7 104.4                      
4 wks 280.7   21.5   28.0 63.5 84.3 95.6 --    --                         
37° C./80% RH                                                      
2 wks 283.2   16.6   39.1 60.5 80.1 89.8  99.8 103.4                      
4 wks 281.3    4.6   26.6 53.7 71.4 82.1 --    --                         
______________________________________
From the results set forth above, it is apparent that under dry conditions at 37° C., the dissolution of Example 4 did not come to the same endpoint as at 37° C./80% RH. Thus, the combination of both moisture and heat was required to complete the curing.
EXAMPLES 5-7
To test the effectiveness of high temperature (60° C.), high humidity curing as an effective process of stabilizing plasticized ethylcellulose controlled release films, Examples 5-7 were manufactured at different levels of Aquacoat® load.
In each of Examples 5-7, hydromorphone beads were made according to Example 1. Thereafter, overcoatings of 5% w/w, 10% w/w, and 15% w/w were applied to Examples 5-7 respectively, according to the formulas set forth in Tables 18-20:
              TABLE 18                                                    
______________________________________                                    
Composition of Ex. 5 After Coating                                        
Ingredient     Percent       Amt/Unit                                     
______________________________________                                    
Hydromorphone beads                                                       
               84.2%          84.2 mg                                     
Aquacoat ® ECD 30                                                     
               4.7%           4.2 mg                                      
Triethyl citrate                                                          
               0.9%           0.84 mg                                     
               100%          89.24 mg                                     
______________________________________                                    

              TABLE 19                                                    
______________________________________                                    
Composition of Ex. 6 After Coating                                        
Ingredient     Percent       Amt/Unit                                     
______________________________________                                    
Hydromorphone beads                                                       
               89.3%         84.2 mg                                      
Aquacoat ® ECD 30                                                     
               8.9%           8.4 mg                                      
Triethyl citrate                                                          
               1.8%           1.7 mg                                      
               100%          94.3 mg                                      
______________________________________                                    

              TABLE 20                                                    
______________________________________                                    
Composition of Ex. 7 After Coating                                        
Ingredient     Percent       Amt/Unit                                     
______________________________________                                    
Hydromorphone beads                                                       
               84.8%         84.2 mg                                      
Aquacoat ® ECD 30                                                     
               12.7%         12.6 mg                                      
Triethyl citrate                                                          
               0.9%           2.5 mg                                      
               100%          99.3 mg                                      
______________________________________
All three batches were cured in water loaded desiccators in a 60° C. oven. These batches were placed on screen trays in these desiccators after the Aquacoat® film was applied to the HPMC overcoated hydromorphone HCl bead. The desiccators containing the Aquacoat®-coated beads were then placed in a 60° C. oven for 72 hours. Thereafter, the batches were removed from the ovens. The beads appeared moist and therefore were dried in a lab line fluid bed dryer for one hour. They were then overcoated with 5% w/w Opadry® Y-5-1442 light pink in a Wurster insert.
Stability studies on Examples 5-7 show the initial dissolutions to be the same as dissolutions done on samples placed at 37° C./80% RH conditions. The results are provided in Tables 21-23 below:
              TABLE 21                                                    
______________________________________                                    
Dissolution (Time) - 5% Aquacoat ®                                    
Time  Wt                                                                  
(Days)                                                                    
      (mg)   1 hr   2 hr 4 hr 8 hr 12 hrs                                 
                                         18 hrs                           
                                               24 hrs                     
______________________________________                                    
Initial                                                                   
      190    39.8   57.4 73.0 88.0 93.8  98.0  95.6                       
28    191    33.4   54.6 71.9 84.2 89.8  94.6  96.4                       
______________________________________                                    

              TABLE 22                                                    
______________________________________                                    
Dissolution (Time) - 10% Aquacoat ®                                   
Time  Wt                                                                  
(Days)                                                                    
      (mg)   1 hr   2 hr 4 hr 8 hr 12 hrs                                 
                                         18 hrs                           
                                               24 hrs                     
______________________________________                                    
Initial                                                                   
      200.3  7.5    27.9 48.5 68.1 76.2  90.3  88.9                       
28    210    9.9    32.4 52.6 67.8 77.9  85.9  90.9                       
______________________________________                                    

              TABLE 23                                                    
______________________________________                                    
Dissolution (Time) - 15% Aquacoat ®                                   
Time  Wt                                                                  
(Days)                                                                    
      (mg)   1 hr   2 hr 4 hr 8 hr 12 hrs                                 
                                         18 hrs                           
                                               24 hrs                     
______________________________________                                    
Initial                                                                   
      210    5.4    13.9 38.0 57.8 68.4  78.6  81.3                       
28    207.3  9.5    23.8 43.4 58.8 67.8  77.0  81.3                       
______________________________________
EXAMPLE 8
In Example 8, Hydromorphone beads overcoated with 10% of the Aquacoat® are prepared in accordance with Example 6. The hydromorphone beads of Example 8 have the following formula set forth in Table 24 below:
              TABLE 24                                                    
______________________________________                                    
Ingredient        Percent  Amt/Unit                                       
______________________________________                                    
Hydromorphone beads                                                       
                  89.3%    84.2 mg                                        
Aquacoat ® ECD30                                                      
                  8.9%     8.4 mg                                         
Triethyl citrate  1.8%     1.7 mg                                         
                  100%     94.3 mg                                        
______________________________________
To test the effectiveness of curing at a lower relative humidity compared to Example 6, the above beads were cured for 72 hours at 60° C. at 60% relative humidity (rather than 85%RH). Similar initial results were obtained for Example 8 as compared to Example 6, thus indicating that the curing step can also be completed at a lower relative humidity. The results are set forth in Table 25 below:
              TABLE 25                                                    
______________________________________                                    
Dissolution (Time) - 10% Aquacoat ®                                   
Example                                                                   
       1 hr   2 hr   4 hr 8 hr  12 hr 18 hr 24 hr                         
______________________________________                                    
Ex. 8  7.5    27.9   48.5 68.1  76.2  90.3  88.9                          
Ex. 6  1.1    18.9   45.0 65.0  76.0  85.8  91.5                          
______________________________________
EXAMPLES 9-10
Hydromorphone HC1 beads were prepared made by spraying a suspension of Hydromorphone HC1 and Opadry® Y-5-1442 light pink (20% w/w) onto nu-pariel 18/20 beads, in accordance with the method set forth in Example 1. These beads were then further coated with Opadry® Y-5-1442 light pink (15% w/w). These beads were then further coated with the Surelease® at a level of 10% weight gain. The formula of the coated bead is set forth in Table 26:
              TABLE 26                                                    
______________________________________                                    
Ingredient        mg/dose  Percent                                        
______________________________________                                    
Hydromorphone HCl 4.0 mg   4.32%                                          
NuPariel beads 18/20                                                      
                  74.0 mg  79.91%                                         
Opadry light pink 6.2 mg   6.70%                                          
Surelease         8.4 mg   9.07%                                          
                  92.6 mg  100%                                           
______________________________________
The batch was then divided into two portions. Example 9 was cured at 60° C./85% RH for 3 days (72 hours), and then dried in a fluid bed dryer for 30 minutes at 60° C. to dry off the excess moisture. These beads were then overcoated with 5% Opadry light pink. Example 10 was left uncured.
Both Examples 9 and 10 were then filled into hard gelatin capsules at a strength of 4 mg hydromorphone per capsule and stored for 3 months at 37° C./80% RH. Dissolution studies were conducted (pursuant to the method set forth for Example 1) initially for both Examples 9 and 10 and again after the 3 month storage at 37° C./85% RH. The results are set forth in Tables 27 and 28 below:
              TABLE 27                                                    
______________________________________                                    
Example 9                                                                 
                     3 Months                                             
Time         Initial at 37° C./80% RH                              
______________________________________                                    
1             4.7     6.5                                                 
4            42.3    56.0                                                 
8            64.9    75.0                                                 
12           77.2     83.19                                               
______________________________________                                    

              TABLE 29                                                    
______________________________________                                    
Example 10                                                                
                     3 Months                                             
Time         Initial at 37° C./80% RH                              
______________________________________                                    
1             1.6     4.5                                                 
4            12.0    61.9                                                 
8            47.8    79.0                                                 
12           66.7    87.7                                                 
______________________________________
The results indicate that despite the expected differences in initial release rates caused by the use of a different aqueous dispersion of ethylcellulose (Surelease® as compared to Aquacoat®), the curing step as described above for Example 9 still significantly stabilized the product in comparison to the uncured product of Example 10. The relatively faster controlled release rate of the Examples using Aquacoat® as compared to Surelease® may be due to the lesser degree of plasticization during the preparation of the coating formulation. However, products using either coating may be modified to obtain satisfactory results.
EXAMPLE 11
The following example illustrates the stabilization of morphine beads in accordance with the present invention.
A suspension of morphine sulphate and HPMC (Opadry® Clear Y-5-7095) was applied onto 18/20 mesh Nu-pariel beads in a fluid bed granulator with a Wurster insert, at 60° C. A HPMC purple color suspension (Opadry® lavender YS-1-4729) was then applied as an overcoat at the same temperature. The beads were then overcoated to a 5% weight gain with Aquacoat® and triethyl citrate as a plasticizer at 60° C. inlet. The beads were then cured in an oven at 60° C./100% relative humidity for three days. The beads were then dried in the fluid bed granulator at 60° C., and an overcoat of HPMC with a purple color was then applied using the Worster column.
The beads were then filled into hard gelatin capsules at a strength of 30 mg morphine sulphate per capsule. The final formula, set forth in Table 29 thus became:
              TABLE 29                                                    
______________________________________                                    
Ingredient         mg/capsule Percent                                     
______________________________________                                    
Morphine sulphate 5H.sub.2 O                                              
                   30.0       8.51%                                       
Nu-pariel beads 18/20                                                     
                   255.0      72.36%                                      
Opadry ® Clear Y-5-7095                                               
                   15.0       4.26%                                       
Opadry ® Lavender YS-1-4729                                           
                   15.8       4.48%                                       
Aquacoat ® ECD30 (solids)                                             
                   15.8       4.48%                                       
Triethyl citrate    3.2       0.91%                                       
Opadry Lavender Y-S-1-4729                                                
                   17.6       4.99%                                       
                   352.4      100%                                        
______________________________________
An initial dissolution of the capsules was conducted using the USP paddle method at 100 rpm in 900 ml of water, and again after storage at 37° C./80% relative humidity, and at 60° C. dry for one month. It was observed that a stable product was made. The results are set forth in Table 30:
              TABLE 30                                                    
______________________________________                                    
Percent Morphine Dissolved                                                
                    37° C./80% RH                                  
                                60° C.                             
Time                after       after                                     
Hrs    Initial      1 Mo        1 Mo                                      
______________________________________                                    
1      15.7         16.6        15.3                                      
4      53.0         51.4        54.9                                      
8      84.4         83.3        90.4                                      
12     96.5         94.4        96.9                                      
______________________________________
EXAMPLE 12
A second experiment was conducted with morphine as described in Example 11; however, the retardant Aquacoat® layer was applied to a 15% weight gain to develop a slower releasing morphine product. The final formulation is set forth in Table 31:
              TABLE 31                                                    
______________________________________                                    
Ingredient         Mg/capsule Percent                                     
______________________________________                                    
Morphine sulphate 5H.sub.2 O                                              
                   30.0       7.65%                                       
Nu-pariel beads 18/20                                                     
                   255.0      65.0%                                       
Opadry ® Clear Y-5-7095                                               
                   15.0       3.82%                                       
Opadry ® Lavender YS-1-4729                                           
                   15.8       4.03%                                       
Aquacoat ® ECD30 (solids)                                             
                   47.4       12.08%                                      
Triethyl citrate    9.5       2.42%                                       
Opadry ® Lavender Y-S-1-4729                                          
                   19.6       5.00%                                       
                   392.3      100%                                        
______________________________________
An initial dissolution of the 30 mg morphine sulphate capsules was conducted as described in Example 10 and again after storage at 37° C./100% relatively humidity and 60° C. dry for one month. It was again observed that a stable product was made. The results are set forth in Table 32 below:
              TABLE 32                                                    
______________________________________                                    
Percent Morphine Dissolved                                                
Time               37° C./80% RH                                   
                               60° C.                              
Hrs    Initial     After 1 Mo  After 1 Mo                                 
______________________________________                                    
1      0            3.1        0                                          
4      18.1        19.4        17.8                                       
8      49.2        49.4        45.7                                       
12     66.3        68.2        65.9                                       
______________________________________
EXAMPLES 13-14
In Example 13, the applicability of another medicament, theophylline, having very different physical properties compared to hydromorphone is demonstrated.
Theophylline hydrous and colloidal silicona dioxide were first mixed together in a high shear mixer, then sieved using a Jet sieve to enhance flowability. Using a fluid bed granulator equipped with a rotor processor, sugar spheres were layered with the theophylline/colloidal silicon dioxide mixture using a PVP (C-30) solution. Layering was continued until an approximately 78% load was obtained.
The formula of the 400 mg theophylline beads when filled into capsules is set forth in Table 33 as follows:
              TABLE 33                                                    
______________________________________                                    
                Mg/unit capsules                                          
______________________________________                                    
Theophylline hydrous                                                      
                  440.0                                                   
(equivalent to 400 mg                                                     
anhydrous theophylline)                                                   
Colloidal silicon dioxide                                                 
                   0.4                                                    
Sugar spheres 30/35 mesh                                                  
                  110.0                                                   
PVP (C-30)         13.5                                                   
                  563.9                                                   
______________________________________
These spheres were then overcoated with a dibutylsebecate plasticized Aquacoat® ECD 30 retardant to a 5% weight gain in the Wurster column in a fluid bed granulator. A portion of the spheres was not cured, and another portion was stored at 60° C. and 100% relative humidity for 72 hours. The following results set forth in Table 34 were obtained:
              TABLE 34                                                    
______________________________________                                    
        1 hr 2 hr   3 hr   4 hr 6 hr  8 hr 24 hr                          
______________________________________                                    
Initial   9.0    92.8   9.46 95.4 97.8  98.0 100.0                        
(uncured)                                                                 
72 hours at                                                               
          3.2     5.3   7.0   7.9 11.0  14.1  35.8                        
60° C./85% RH                                                      
______________________________________
From the above, it was determined that theophylline spheroids coated with Aquacoat® also are not stable and need to be cured. After storage at 72 hours at 60° C. and 85% relative humidity, a dramatic drop in dissolution rate occurred; however, such conditions may, in some instances, represent "ideal" curing conditions to form a stable product. In view of this goal, the dissolution data after 72 hours at 60° C./85%RH provides too slow a dissolution profile for theophylline.
Therefore, Example 14 was prepared in order to attempt to improve the dissolution profile of the formulation via incorporation of this new curing step, and the coating was altered in order to increase the dissolution rate to 100% theophylline dissolved in 12 hours.
Example 14 was prepared as follows. Theophylline powder layered beads were made as described in Example 13 and were then overcoated with a plasticized Aquacoat® ECD 30 retardant, which, and for this example, included 10% HPMC (hydroxypropyl methyl cellulose). This was done so that the release of theophylline would be faster than Example 13. The inclusion of HPMC to speed up dissolution is known in the prior art. The retardant layer was also coated to a 6% weight gain in the Worster column of the fluid bed granulator.
The coated beads were then cured for 72 hours at 60° C./85% relative humidity. A dissolution study was conducted initially, and once again after the beads were stored at 37° C./80% relative humidity for three months. It was observed that the stability of the dissolution of the theophylline from the formulation of Example 14 improved dramatically compared to Example 13. It was further observed that by inclusion of HPMC in the retardant layer in the proportions of Aquacoat® ECD 30 (solids):HPMC of 9:1, coated to a 6% weight gain, the dissolution rate of the formulation was increased to 100% theophylline dissolved in 12 hours. The results are set forth in detail in Table 35 below:
              TABLE 35                                                    
______________________________________                                    
          1 hr   2 hr   4 hr     8 hr 12 hr                               
______________________________________                                    
Cured       17       38     68     97   100                               
Initial                                                                   
Storage at  13       31     60     94   100                               
37° C./80% RH                                                      
for 3 months                                                              
______________________________________
The examples provided above are not meant to be exclusive. Many other variations of the present invention would be obvious to those skilled in the art.
For example, although the present invention has been described with respect to the most preferred hydrophobic polymer, ethylcellulose, it is contemplated that other hydrophobic polymers, such as other cellulose derivatives, may also be useful in conjunction with the present invention. Such other hydrophobic polymers are considered to be within the scope of the appended claims.
Likewise, as previously explained, one skilled in the art will recognize that necessary curing conditions may be change somewhat depending upon the particular formulation (including the amount of overcoating, the properties of the therapeutically active agent, and the like), such that a stabilized product is obtained via a modified range with regard to temperature, humidity and time. Such variations are contemplated to be within the scope of the appended claims.

Claims (34)

What is claimed is:
1. A method for obtaining a stabilized controlled release formulation comprising a substrate coated with an aqueous dispersion of ethylcellulose, comprising
preparing a solid substrate comprising a therapeutically active agent,
overcoating said substrate with a sufficient amount of an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of said therapeutically active agent when said coated substrate is exposed to aqueous solutions,
curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of ethylcellulose and at a relative humidity from about 60% to about 100 %, and continuing the curing until an endpoint is reached at which said cured coated substrate provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of one month at a temperature of 37° C. and at a relative humidity of 80%.
2. The method of claim 1, further comprising preparing said solid substrate for oral administration by overcoating said therapeutically active agent onto the surface of pharmaceutically acceptable inert beads, and after overcoating and curing said beads, preparing an oral dosage form by placing a sufficient quantity of cured coated beads into a capsule to provide a therapeutic effect when administered.
3. The method of claim 2, wherein said coated beads are coated to a weight gain from about 5 to about 15 percent, and are thereafter cured for about 48 to about 72 hours, until the endpont is reached.
4. The product prepared according to the method of claim 2.
5. The method of claim 1, wherein said substrate comprises a tablet core.
6. The product prepared according to the method of claim 1.
7. The method of claim 1, further comprising overcoating said substrate comprising said therapeutically active agent with a barrier agent prior to overcoating with said aqueous dispersion of ethylcellulose.
8. The method of claim 7, wherein said barrier agent comprises hydroxypropyl methylcellulose.
9. The method of claim 1, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
10. The method of claim 1, wherein said therapeutically active agent is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.
11. The method of claim 1, wherein said therapeutically active agent is theophylline.
12. The product prepared according to the method of claim 1.
13. A stabilized solid controlled release dosage form comprising a substrate comprising a therapeutically active agent, said substrate overcoated with an aqueous dispersion of plasticized ethylcellulose and cured at a temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized ethylcellulose and at a relative humidity from about 60% to about 100% until an endpoint is reached at which said cured coated substrate provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of one month at a temperature of 37° C. and at a relative humidity of 80%.
14. The stabilized solid controlled release dosage form of claim 13, wherein said therapeutically active agent is overcoated with said aqueous dispersion of ethylcellulose to a weight gain level from about 5 to about 15 percent.
15. The stabilized solid controlled release dosage form of claim 14, wherein said substrate further comprises inert pharmaceutically acceptable beads onto which said therapeutically active agent is coated.
16. The stabilized solid controlled release dosage form of claim 15, wherein a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.
17. The stabilized solid controlled release dosage form of claim 13, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
18. The stabilized solid controlled release dosage form of claim 13, wherein said therapeutically active agent is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphone, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.
19. The stabilized solid controlled release dosage form of claim 13, wherein said therapeutically active agent is theophylline.
20. A stabilized controlled release solid dosage form for oral administration, comprising a plurality of inert pharmaceutically acceptable beads coated with a therapeutically active agent, and overcoated with an aqueous dispersion of plasticized ethylcellulose to a thickness effective to obtain a controlled release of said therapeutically active agent when said solid dosage form is exposed to aqueous solutions, said overcoated beads included in said formulation in an amount sufficient to provide a desired therapeutic effect,
said overcoated beads cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100%, until an endpoint is reached at which said cured overcoated beads provide a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of one month at a temperature of 37° C. and at a relative humidity of 80%.
21. The stabilized controlled release solid dosage form of claim 20, wherein said beads are coated with said aqueous dispersion of plasticized ethylcellulose to a weight gain from about 5 to about 15 percent, and said beads are thereafter cured for about 48 to about 72 hours, until the endpoint is reached.
22. The stabilized solid controlled release dosage form of claim 20, wherein a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.
23. The stabilized solid controlled release dosage form of claim 20, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
24. The stabilized solid controlled release dosage form of claim 20, wherein said therapeutically active agent is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.
25. The stabilized solid controlled release dosage form of claim 20, wherein said therapeutically active agent is theophylline.
26. A solid dosage form comprising a plurality of inert pharmaceutically acceptable beads comprising a therapeutically active agent overcoated with an aqueous dispersion of ethylcellulose to a weight gain sufficient to obtain a controlled release of said therapeutically active agent when said dosage form is exposed to aqueous solutions, said solid dosage form being cured after said overcoating is applied at a temperature greater than the glass transition temperature of said aqueous dispersion of ethylcellulose and at a relative humidity from about 60% to about 100% for a time period from about 48 hours to about 72 hours, until said cured coated dosage form exhibits a stable in-vitro release of said therapeutically active agent when exposed to accelerated storage conditions of one month at about 37° C. and 80% relative humidity.
27. The solid dosage form of claim 26, wherein said beads are coated with said aqueous dispersion of plasticized ethylcellulose to a weight gain from about 5 to about 15 percent.
28. The solid dosage form of claim 27, wherein said coated beads are cured at a temperature of about 60° C. and at a relative humidity of about 85%.
29. The solid dosage form of claim 26, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
30. A method of stabilizing a substrate comprising a therapeutically active agent overcoated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of the therapeutically active agent when the coated substrate is exposed to aqueous solutions, comprising subjecting the coated substrate to curing at a temperature greater than the glass transition temperature of said aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100%, for a period of time necessary to obtain a final product which exhibits a stable in-vitro release of said therapeutically active agent when exposed to accelerated storage conditions of one month at 37° C. and 80% relative humidity.
31. The method of claim 30, further comprising preparing the coated substrate by applying said therapeutically active agent onto the surface of a pharmaceutically inert bead, and conducting said curing step by oven curing.
32. The method of claim 30, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, diuretics anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
33. A stabilized solid controlled release dosage form comprising a substrate comprising a therapeutically active agent, said substrate overcoated with an aqueous dispersion of plasticized ethylcellulose to a sufficient weight gain such that a controlled release of said therapeutically active agent is obtained when said dosage form is exposed to aqueous solutions, said overcoated substrate cured at a temperature greater than the glass transition temperature of said aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60 to about 100 percent for a time period necessary to obtain a final product which exhibits a stable in-vitro release of said therapeutically active agent when exposed to accelerated storage conditions of one month at 37° C. and 80% relative humidity.
34. The stabilized solid controlled release dosage form of claim 33, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
US07/814,111 1991-12-24 1991-12-24 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer Expired - Lifetime US5273760A (en)

Priority Applications (45)

Application Number Priority Date Filing Date Title
US07/814,111 US5273760A (en) 1991-12-24 1991-12-24 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
NZ241660A NZ241660A (en) 1991-12-24 1992-02-19 Controlled-release formulations overcoated with plasticised ethylcellulose and cured at elevated temperature and humidity
IN121CA1992 IN173974B (en) 1991-12-24 1992-02-21
ZA921366A ZA921366B (en) 1991-12-24 1992-02-25 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
CA002061824A CA2061824C (en) 1991-12-24 1992-02-25 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
IL10108092A IL101080A (en) 1991-12-24 1992-02-27 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of ethylcellulose
MX9200932A MX9200932A (en) 1991-12-24 1992-03-04 STABILIZED CONTROLLED RELEASE SUBSTRATE THAT HAS A LINING DERIVED FROM A WATER DISPERSION OF HYDROPHOBIC POLYMER.
IE079592A IE920795A1 (en) 1991-12-24 1992-03-12 Stabilized controlled release substrate having a coating¹derived from an aqueous dispersion of hydrophobic polymer
JP4071808A JP3061474B2 (en) 1991-12-24 1992-03-30 Method for obtaining a stable controlled release formulation coated with an aqueous dispersion of a hydrophobic polymer
FI921548A FI921548A (en) 1991-12-24 1992-04-08 STABILIZER, CONTROLLER FRIGOERANDE SUBSTRATE MED EN BELAEGGNING FRAMSTAELLD FRAON EN DISPERSION AV EN HYDROFOB POLYMER
DE69231415T DE69231415T2 (en) 1991-12-24 1992-04-15 Stabilized substrate for controlled release with a coating derived from an aqueous dispersion of a hydrophobic polymer
PT92106519T PT548448E (en) 1991-12-24 1992-04-15 CONTROLLED LIBERATION STABILIZED SUBSTRATE HAVING A COATING DERIVED FROM AQUOSA HYDROFOBIC POLYMER DISPERSION
AT92106519T ATE196079T1 (en) 1991-12-24 1992-04-15 STABILIZED CONTROLLED RELEASE SUBSTRATE HAVING A COATING DERIVED FROM AN AQUEOUS DISPERSION OF A HYDROPHOBIC POLYMER
EP92106519A EP0548448B1 (en) 1991-12-24 1992-04-15 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
DK92106519T DK0548448T3 (en) 1991-12-24 1992-04-15 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
SG1996005933A SG44703A1 (en) 1991-12-24 1992-04-15 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
ES92106519T ES2152221T3 (en) 1991-12-24 1992-04-15 STABILIZED CONTROLLED RELEASE SUBSTRATE THAT HAS A COATING DERIVED FROM A WATERPROOF DISPERSION OF HYDROPHOBE POLYMER.
YU42792A YU48345B (en) 1991-12-24 1992-04-22 A STABILIZED SOLID DOSAGE FORM WITH CONTROLLED RELEASE COATING DERIVATIVES FROM AQUATIC DISPERSION OF ETHYCELLULOSIS AND A PROCEDURE FOR OBTAINING THIS
KR1019920010356A KR100252188B1 (en) 1991-12-24 1992-06-15 Controlled-release formulations coated with aqueous dispersions of hydrophobic polymer
IN462CA1992 IN173298B (en) 1991-12-24 1992-06-29
BR929202982A BR9202982A (en) 1991-12-24 1992-07-31 PROCESS TO OBTAIN A STABILIZED FORMATION OF CONTROLLED RELEASE, SOLID DOSE FORM AND PROCESS TO STABILIZE A SUBSTRATE
AU30024/92A AU652871B2 (en) 1991-12-24 1992-12-08 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
EG80192A EG20083A (en) 1991-12-24 1992-12-23 Stabilized controlled release substracte having a cooting derived from an aqueous dispersion of hydropholic polymer
NO19925016A NO312577B1 (en) 1991-12-24 1992-12-23 A process for preparing a controlled release stabilized formulation comprising a substrate coated with an aqueous dispersion of ethyl cellulose
US08/081,618 US5472712A (en) 1991-12-24 1993-06-23 Controlled-release formulations coated with aqueous dispersions of ethylcellulose
IN455CA1994 IN177789B (en) 1991-12-24 1994-06-15
IN900CA1994 IN178679B (en) 1991-12-24 1994-10-31
US08/508,246 US5968551A (en) 1991-12-24 1995-07-27 Orally administrable opioid formulations having extended duration of effect
US08/561,829 US5958459A (en) 1991-12-24 1995-11-27 Opioid formulations having extended controlled released
US08/667,052 US5681585A (en) 1991-12-24 1996-06-20 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
IN1452CA1996 IN182215B (en) 1991-12-24 1996-08-13
US08/899,924 US6129933A (en) 1991-12-24 1997-07-24 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
HK98104870A HK1005686A1 (en) 1991-12-24 1998-06-04 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US09/390,719 US6294195B1 (en) 1991-12-24 1999-09-07 Orally administrable opioid formulations having extended duration of effect
US09/469,478 US6316031B1 (en) 1991-12-24 1999-12-22 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
GR20000402654T GR3034951T3 (en) 1991-12-24 2000-11-30 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer.
US09/891,882 US6572885B2 (en) 1991-12-24 2001-06-26 Orally administrable opioid formulations having extended duration of effect
US10/054,726 US6905709B2 (en) 1991-12-24 2001-11-12 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US10/392,586 US7270831B2 (en) 1991-12-24 2003-03-20 Orally administrable opioid formulations having extended duration of effect
US10/731,678 US20040121001A1 (en) 1991-12-24 2003-12-08 Orally adminstrable opioid formulations having extended duration of effect
US10/871,251 US7316821B2 (en) 1991-12-24 2004-06-18 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US11/840,452 US20080181941A1 (en) 1991-12-24 2007-08-17 Orally administrable opioid formulations having extended duration of effect
US11/856,610 US20080044482A1 (en) 1991-12-24 2007-09-17 Orally administrable opioid formulations having extended duration of effect
US11/983,173 US20080063712A1 (en) 1991-12-24 2007-11-07 Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US12/207,702 US20090068269A1 (en) 1991-12-24 2008-09-10 Orally adminstrable opioid formulations having extended duration of effect

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US08/081,618 Continuation-In-Part US5472712A (en) 1991-12-24 1993-06-23 Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US8624893A Continuation-In-Part 1991-12-24 1993-07-01

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EP (1) EP0548448B1 (en)
JP (1) JP3061474B2 (en)
KR (1) KR100252188B1 (en)
AT (1) ATE196079T1 (en)
AU (1) AU652871B2 (en)
BR (1) BR9202982A (en)
CA (1) CA2061824C (en)
DE (1) DE69231415T2 (en)
DK (1) DK0548448T3 (en)
EG (1) EG20083A (en)
ES (1) ES2152221T3 (en)
FI (1) FI921548A (en)
GR (1) GR3034951T3 (en)
HK (1) HK1005686A1 (en)
IE (1) IE920795A1 (en)
IL (1) IL101080A (en)
MX (1) MX9200932A (en)
NO (1) NO312577B1 (en)
NZ (1) NZ241660A (en)
PT (1) PT548448E (en)
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Cited By (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580578A (en) * 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5626872A (en) * 1992-06-16 1997-05-06 Roemmers S.A.I.C.F. Pharmaceutical soft capsules containing lysine clonixinate and a process for their preparation
US5637319A (en) * 1995-03-01 1997-06-10 Takada; Kanji Controlled-release preparations
US5641516A (en) * 1992-08-13 1997-06-24 Basf Aktiengesellschaft Compositions which contain active substances and are in the form of solid particles
US5662933A (en) * 1993-09-09 1997-09-02 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US5672360A (en) * 1993-11-23 1997-09-30 Purdue Pharma, L.P. Method of treating pain by administering 24 hour oral opioid formulations
US5681585A (en) * 1991-12-24 1997-10-28 Euro-Celtique, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5783212A (en) * 1996-02-02 1998-07-21 Temple University--of the Commonwealth System of Higher Education Controlled release drug delivery system
US5843480A (en) * 1994-03-14 1998-12-01 Euro-Celtique, S.A. Controlled release diamorphine formulation
US5849240A (en) * 1993-11-23 1998-12-15 Euro-Celtique, S.A. Method of preparing sustained release pharmaceutical compositions
US5879705A (en) * 1993-07-27 1999-03-09 Euro-Celtique S.A. Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
US5891474A (en) * 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US5891471A (en) * 1993-11-23 1999-04-06 Euro-Celtique, S.A. Pharmaceutical multiparticulates
US5902632A (en) * 1995-01-31 1999-05-11 Mehta; Atul M. Method of preparation of controlled release nifedipine formulations
US5945125A (en) * 1995-02-28 1999-08-31 Temple University Controlled release tablet
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US6048548A (en) * 1993-09-09 2000-04-11 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems-amorphous drugs
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
US6066339A (en) * 1997-10-17 2000-05-23 Elan Corporation, Plc Oral morphine multiparticulate formulation
US6068855A (en) 1994-11-03 2000-05-30 Euro-Celtique S. A. Pharmaceutical composition containing a fusible carrier and method for producing the same
US6093420A (en) * 1996-07-08 2000-07-25 Edward Mendell Co., Inc. Sustained release matrix for high-dose insoluble drugs
US6103261A (en) * 1993-07-01 2000-08-15 Purdue Pharma Lp Opioid formulations having extended controlled release
US6136343A (en) * 1993-09-09 2000-10-24 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US6193775B1 (en) * 1992-08-13 2001-02-27 Chisso Corporation Coated granular fertilizer
US6254887B1 (en) 1993-05-10 2001-07-03 Euro-Celtique S.A. Controlled release tramadol
WO2001058447A1 (en) * 2000-02-08 2001-08-16 Euro-Celtique, S.A. Controlled-release compositions containing opioid agonist and antagonist
US6306438B1 (en) 1997-07-02 2001-10-23 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
US20010038856A1 (en) * 1994-07-07 2001-11-08 Sonya Merrill Hydromorphone therapy
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US6399096B1 (en) 1995-09-22 2002-06-04 Euro-Celtique S.A. Pharmaceutical formulation
US20020099064A1 (en) * 1997-09-17 2002-07-25 Burch Ronald M. Analgesic combination of oxycodone and T-614
EP1227798A1 (en) * 1999-10-29 2002-08-07 Euro-Celtique S.A. Controlled release hydrocodone formulations
US6475494B2 (en) 1997-12-22 2002-11-05 Euro-Celtique S.A. Opioid agonist/antagonist combinations
CN1104910C (en) * 1995-10-19 2003-04-09 昆士兰大学 Production of analgesic synergy by co-administration of sub-analgesic doses of a mu opioid agonist and kappa-2 opioid agonist
US20030077324A1 (en) * 2001-06-08 2003-04-24 Nostrum Pharmaceuticals, Inc. Control release formulation containing a hydrophobic material as the sustained release agent
US6555139B2 (en) 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
US6565877B1 (en) 1999-06-11 2003-05-20 Ranbaxy Laboratories Limited Taste masked compositions
US20030099711A1 (en) * 2001-08-29 2003-05-29 David Meadows Sustained release preparations
WO2003063834A1 (en) * 2002-02-01 2003-08-07 Pacific Corporation Multi-stage oral drug controlled-release system
EP1337244A1 (en) * 2000-10-30 2003-08-27 Euroceltique S.A. Controlled release hydrocodone formulations
US20030190358A1 (en) * 1994-11-04 2003-10-09 Benjamin Oshlack Sustained release hydromorphone formulations exhibiting bimodal characteristics
US6635277B2 (en) 2000-04-12 2003-10-21 Wockhardt Limited Composition for pulsatile delivery of diltiazem and process of manufacture
US20040029962A1 (en) * 1997-12-12 2004-02-12 Chih-Ming Chen HMG-COA reductase inhibitor extended release formulation
US6716449B2 (en) 2000-02-08 2004-04-06 Euro-Celtique S.A. Controlled-release compositions containing opioid agonist and antagonist
US6726930B1 (en) 1993-09-09 2004-04-27 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US20040170684A1 (en) * 1999-09-30 2004-09-02 Penwest Pharmaceuticals Co. Sustained release matrix systems for highly soluble drugs
US6800329B2 (en) * 1999-02-12 2004-10-05 Lts Lohmann Therapie-Systeme Ag Method for producing film-type dosage
US6806294B2 (en) 1998-10-15 2004-10-19 Euro-Celtique S.A. Opioid analgesic
WO2004093801A2 (en) 2003-04-21 2004-11-04 Euro-Celtique S.A. Pharmaceutical products
US20050084540A1 (en) * 2003-10-17 2005-04-21 Indranil Nandi Taste masking antibiotic composition
WO2005060968A1 (en) 2003-12-11 2005-07-07 Sepracor Inc. Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US20050191351A1 (en) * 2003-11-04 2005-09-01 Shire Laboratories, Inc. Once daily dosage forms of trospium
US20050245483A1 (en) * 2002-04-05 2005-11-03 Bianca Brogmann Matrix for sustained, invariant and independent release of active compounds
US20060052432A1 (en) * 2002-09-20 2006-03-09 Julius Remenar Pharmaceutical compositions with improved dissolution
US20060141035A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-COA reductase inhibitor extended release formulation
US20060148877A1 (en) * 2002-11-26 2006-07-06 Transform Pharmaceuticals, Inc. Pharmaceutical formulations of celcoxib
US20060173029A1 (en) * 2004-03-30 2006-08-03 Euro-Celtique S.A. Oxycodone hydrochloride having less than 25 ppm 14- hydroxycodeinone
US20070026078A1 (en) * 2002-02-15 2007-02-01 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions
US20070128279A1 (en) * 1998-03-06 2007-06-07 Alza Corporation Extended Release Dosage Form
US20070184198A1 (en) * 2006-02-07 2007-08-09 Fmc Corporation Coating process to produce controlled release coatings
US20070215511A1 (en) * 2006-03-16 2007-09-20 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US20070259033A1 (en) * 2003-09-26 2007-11-08 Evangeline Cruz Controlled release formulations exhibiting an ascending rate of release
US20070259045A1 (en) * 2005-01-28 2007-11-08 Euro-Celtique S.A. Alcohol Resistant Dosage Forms
EP1894562A1 (en) 2002-08-15 2008-03-05 Euro-Celtique S.A. Pharmaceutical compositions
US20080132532A1 (en) * 2004-09-01 2008-06-05 Curtis Wright Opioid Dosage Forms Having Dose Proportional Steady State Cave and Auc and Less Than Dose Proportional Single Dose Cmax
US7384653B2 (en) 2001-08-06 2008-06-10 Purdue Pharma L.P. Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20080146601A1 (en) * 2006-12-14 2008-06-19 Johnson Matthey Public Limited Company Method for making analgesics
EP1935421A1 (en) 2000-02-08 2008-06-25 Euro-Celtique S.A. Controlled-release compositions containing opioid agonist and antagonist
EP1961421A1 (en) 2004-06-08 2008-08-27 Euro-Celtique S.A. Opioids for the treatment of the chronic obstructive pulmonary disease (COPD)
EP1967191A1 (en) 1998-12-17 2008-09-10 Euro-Celtique S.A. Controlled/modified release oral methylphenidate formulations
EP2011485A2 (en) 2001-05-02 2009-01-07 Euro-Celtique S.A. Once-a-day oxycodone formulations
US20090088443A1 (en) * 2002-02-15 2009-04-02 Julius Remenar Novel crystalline forms of conazoles and methods of making and using the same
US20090169626A1 (en) * 2006-01-27 2009-07-02 Euro-Celtique S.A. Tamper resistant dosage forms
US20090214642A1 (en) * 2006-03-31 2009-08-27 Lek Pharmaceuticals D.D. Coated formulations for tolterodine
US7682633B2 (en) 2006-06-19 2010-03-23 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
WO2010036777A1 (en) 2008-09-25 2010-04-01 Isp Investments Inc. Smooth, high solids tablet coating composition
EP2184058A1 (en) 2003-09-26 2010-05-12 Alza Corporation Drug coating providing high drug loading and methods for providing the same
US7740881B1 (en) 1993-07-01 2010-06-22 Purdue Pharma Lp Method of treating humans with opioid formulations having extended controlled release
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7829120B2 (en) 2005-09-09 2010-11-09 Labopharm Inc. Trazodone composition for once a day administration
EP2255808A2 (en) 2004-06-08 2010-12-01 Euro-Celtique S.A. Opioids for the treatment of the restlessness of the lower limbs
EP2298303A1 (en) 2003-09-25 2011-03-23 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
US7914818B2 (en) 2001-08-06 2011-03-29 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US20110104214A1 (en) * 2004-04-15 2011-05-05 Purdue Pharma L.P. Once-a-day oxycodone formulations
US7943173B2 (en) 2001-07-18 2011-05-17 Purdue Pharma L.P. Pharmaceutical combinations of oxycodone and naloxone
EP2339328A2 (en) 2002-12-30 2011-06-29 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of celecoxib
US20110172259A1 (en) * 2005-02-28 2011-07-14 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
US7988998B2 (en) 2002-10-25 2011-08-02 Labopharm Inc. Sustained-release tramadol formulations with 24-hour efficacy
US20110223244A1 (en) * 2010-03-09 2011-09-15 Elan Pharma International Limited Alcohol resistant enteric pharmaceutical compositions
US8173199B2 (en) * 2002-03-27 2012-05-08 Advanced Cardiovascular Systems, Inc. 40-O-(2-hydroxy)ethyl-rapamycin coated stent
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
US8182836B2 (en) 2003-04-08 2012-05-22 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
WO2012080833A2 (en) 2010-12-13 2012-06-21 Purdue Pharma L.P. Controlled release dosage forms
US8337888B2 (en) 2001-08-06 2012-12-25 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8354124B2 (en) 2002-12-13 2013-01-15 Durect Corporation Oral drug delivery system
US8362062B2 (en) 2002-02-15 2013-01-29 Mcneil-Ppc, Inc. Pharmaceutical compositions with improved dissolution
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US8465774B2 (en) 2001-08-06 2013-06-18 Purdue Pharma L.P. Sequestered antagonist formulations
EP2606880A1 (en) * 2011-12-23 2013-06-26 LEK Pharmaceuticals d.d. Coating process with aqueous latex coating
US8487002B2 (en) 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
US8541026B2 (en) 2004-09-24 2013-09-24 Abbvie Inc. Sustained release formulations of opioid and nonopioid analgesics
WO2013164122A1 (en) * 2012-05-02 2013-11-07 Capsugel France SAS Aqueous dispersions of controlled release polymers and shells and capsules thereof
US8623409B1 (en) 2010-10-20 2014-01-07 Tris Pharma Inc. Clonidine formulation
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
WO2014013311A1 (en) 2012-07-16 2014-01-23 Rhodes Technologies Process for improved opioid synthesis
WO2014013313A1 (en) 2012-07-16 2014-01-23 Rhodes Technologies Process for improved opioid synthesis
US8685444B2 (en) 2002-09-20 2014-04-01 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and methods
US8709476B2 (en) 2003-11-04 2014-04-29 Supernus Pharmaceuticals, Inc. Compositions of quaternary ammonium compounds containing bioavailability enhancers
US8808740B2 (en) 2010-12-22 2014-08-19 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US8969369B2 (en) 2001-05-11 2015-03-03 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US20150064248A1 (en) * 2007-08-13 2015-03-05 Inspirion Delivery Technologies, Llc Abuse resistant forms of extended release hydromorphone, method of use and method of making
US9062063B1 (en) 2014-03-21 2015-06-23 Johnson Matthey Public Limited Company Forms of oxymorphone hydrochloride
WO2015107472A1 (en) 2014-01-15 2015-07-23 Rhodes Technologies Process for improved oxymorphone synthesis
WO2015107471A1 (en) 2014-01-15 2015-07-23 Rhodes Technologies Process for improved oxycodone synthesis
US9120800B2 (en) 2013-08-02 2015-09-01 Johnson Matthey Public Limited Company Process for the preparation of oxymorphone alkaloid and oxymorphone salts
WO2015138200A1 (en) 2014-03-11 2015-09-17 Fmc Corporation Controlled release composition and method
US9149533B2 (en) 2013-02-05 2015-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
WO2015166472A1 (en) * 2014-05-01 2015-11-05 Sun Pharmaceutical Industries Limited Extended release liquid compositions of metformin
US20150313850A1 (en) * 1998-12-17 2015-11-05 Purdue Pharma Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US9233073B2 (en) 2010-12-23 2016-01-12 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US9271940B2 (en) 2009-03-10 2016-03-01 Purdue Pharma L.P. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
WO2016087952A1 (en) * 2014-12-05 2016-06-09 Sun Pharmaceutical Industries Limited Gastroretentive extended release suspension compositions
WO2016123202A1 (en) 2015-01-29 2016-08-04 Johnson Matthey Public Limited Company Process of preparing low abuk oxymorphone hydrochloride
WO2017015309A1 (en) 2015-07-22 2017-01-26 John Hsu Composition comprising a therapeutic agent and a respiratory stimulant and methods for the use thereof
US9555113B2 (en) 2013-03-15 2017-01-31 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US9592204B2 (en) 2007-12-06 2017-03-14 Durect Corporation Oral pharmaceutical dosage forms
US9616030B2 (en) 2013-03-15 2017-04-11 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9616055B2 (en) 2008-11-03 2017-04-11 Durect Corporation Oral pharmaceutical dosage forms
US9662326B2 (en) 2012-04-17 2017-05-30 Purdue Pharma L.P. Systems for treating an opioid-induced adverse pharmacodynamic response
US9849124B2 (en) 2014-10-17 2017-12-26 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9962336B2 (en) 2014-05-01 2018-05-08 Sun Pharmaceutical Industries Limited Extended release suspension compositions
US9962345B2 (en) 2014-05-01 2018-05-08 Sun Pharmaceutical Industries Limited Oral liquid compositions of guanfacine
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10071089B2 (en) 2013-07-23 2018-09-11 Euro-Celtique S.A. Combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10238803B2 (en) 2016-05-02 2019-03-26 Sun Pharmaceutical Industries Limited Drug delivery device for pharmaceutical compositions
US10258583B2 (en) 2014-05-01 2019-04-16 Sun Pharmaceutical Industries Limited Extended release liquid compositions of guanfacine
US10258235B2 (en) 2005-02-28 2019-04-16 Purdue Pharma L.P. Method and device for the assessment of bowel function
US10285908B2 (en) 2014-07-30 2019-05-14 Sun Pharmaceutical Industries Ltd Dual-chamber pack
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
US10369078B2 (en) 2016-05-02 2019-08-06 Sun Pharmaceutical Industries Limited Dual-chamber pack for pharmaceutical compositions
US10525052B2 (en) 2004-06-12 2020-01-07 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US10633344B2 (en) 2002-03-01 2020-04-28 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
US10646485B2 (en) 2016-06-23 2020-05-12 Collegium Pharmaceutical, Inc. Process of making stable abuse-deterrent oral formulations
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10813886B2 (en) 2013-11-04 2020-10-27 Capsugel Belgium Nv Methods and systems for improved bioavailability of active pharmaceutical ingredients including esomeprazole
US11504345B2 (en) 2014-05-01 2022-11-22 Sun Pharmaceutical Industries Limited Extended release liquid compositions of metformin
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions
US11590081B1 (en) 2017-09-24 2023-02-28 Tris Pharma, Inc Extended release amphetamine tablets
US11918689B1 (en) 2020-07-28 2024-03-05 Tris Pharma Inc Liquid clonidine extended release composition

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266331A (en) † 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
GB2284760B (en) * 1993-11-23 1998-06-24 Euro Celtique Sa A method of preparing pharmaceutical compositions by melt pelletisation
US5472712A (en) * 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
ATE154238T1 (en) * 1992-02-20 1997-06-15 Euro Celtique Sa MEDICINAL PRODUCTS WITH DELAYED RELEASE
SE9301057L (en) † 1993-03-30 1994-10-01 Pharmacia Ab Controlled release preparation
EP0647448A1 (en) * 1993-10-07 1995-04-12 Euroceltique S.A. Orally administrable opioid formulations having extended duration of effect
US6210714B1 (en) 1993-11-23 2001-04-03 Euro-Celtique S.A. Immediate release tablet cores of acetaminophen having sustained-release coating
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
US6245351B1 (en) 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US20020188037A1 (en) * 1999-04-15 2002-12-12 Chudzik Stephen J. Method and system for providing bioactive agent release coating
US6126967A (en) * 1998-09-03 2000-10-03 Ascent Pediatrics Extended release acetaminophen particles
DE19901686A1 (en) * 1999-01-18 2000-07-20 Gruenenthal Gmbh Retarded tramadol preparations with a storage-stable release profile and process for their preparation
US7097850B2 (en) * 2002-06-18 2006-08-29 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
US20040110781A1 (en) * 2002-12-05 2004-06-10 Harmon Troy M. Pharmaceutical compositions containing indistinguishable drug components
ES2337935T3 (en) 2007-11-09 2010-04-30 Acino Pharma Ag COMPRESSED DELAYED ACTION WITH HYDROMORPHONE.
ES2444591T3 (en) 2010-10-28 2014-02-25 Acino Pharma Ag Medication with the active substance hydromorphone with improved storage stability
KR101847947B1 (en) 2013-03-15 2018-05-28 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 Stabilized modified release vitamin d formulation
EP2937096B1 (en) 2014-04-23 2019-08-21 Julius-Maximilians-Universität Würzburg Peptides derived from RS1 which down-regulate glucose absorption after a glucose rich meal and increase insulin sensitivity
US20190389785A1 (en) * 2018-06-11 2019-12-26 Ningbo Weston Powder Pharma Coatings Co., Ltd. Controlled release nutrients by coating

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60166608A (en) * 1984-02-08 1985-08-29 Japan Atom Energy Res Inst Slow-releasing composite having sandwich structure and its preparation
US4600645A (en) * 1985-01-31 1986-07-15 Warner-Lambert Company Process for treating dosage forms
GB2170104A (en) * 1985-01-30 1986-07-30 Warner Lambert Co Coated pharmaceutical dosage forms
US4728513A (en) * 1985-07-31 1988-03-01 Zyma Sa Granular delayed-release form of pharmaceutically active substances
US5019397A (en) * 1988-04-21 1991-05-28 Alza Corporation Aqueous emulsion for pharmaceutical dosage form
US5042842A (en) * 1990-06-26 1991-08-27 Avery International Corporation High security label
US5068110A (en) * 1987-09-29 1991-11-26 Warner-Lambert Company Stabilization of enteric coated dosage form

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60166608A (en) * 1984-02-08 1985-08-29 Japan Atom Energy Res Inst Slow-releasing composite having sandwich structure and its preparation
GB2170104A (en) * 1985-01-30 1986-07-30 Warner Lambert Co Coated pharmaceutical dosage forms
US4600645A (en) * 1985-01-31 1986-07-15 Warner-Lambert Company Process for treating dosage forms
US4728513A (en) * 1985-07-31 1988-03-01 Zyma Sa Granular delayed-release form of pharmaceutically active substances
US5068110A (en) * 1987-09-29 1991-11-26 Warner-Lambert Company Stabilization of enteric coated dosage form
US5019397A (en) * 1988-04-21 1991-05-28 Alza Corporation Aqueous emulsion for pharmaceutical dosage form
US5042842A (en) * 1990-06-26 1991-08-27 Avery International Corporation High security label

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
D. L. Munday, A. R. Fassihi, 5th Congr. Int. Technol. Pharm. vol. 2, pp. 55 60, Changes in Drug Release Rate, Effect of Temperature and Relative Humidity on Polymeric Film Coatings, 1989, Assoc. Pharm. Galenique Ind., Chatenay Malabry, FR. *
D. L. Munday, A. R. Fassihi, 5th Congr. Int. Technol. Pharm. vol. 2, pp. 55-60, Changes in Drug Release Rate, Effect of Temperature and Relative Humidity on Polymeric Film Coatings, 1989, Assoc. Pharm. Galenique Ind., Chatenay Malabry, FR.

Cited By (550)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US6316031B1 (en) * 1991-12-24 2001-11-13 Purdue Pharma Lp Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US6572885B2 (en) * 1991-12-24 2003-06-03 Euro-Celtique, S.A. Orally administrable opioid formulations having extended duration of effect
US7270831B2 (en) 1991-12-24 2007-09-18 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US6905709B2 (en) 1991-12-24 2005-06-14 Purdue Pharma, Lp Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US6294195B1 (en) * 1991-12-24 2001-09-25 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5681585A (en) * 1991-12-24 1997-10-28 Euro-Celtique, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US7316821B2 (en) 1991-12-24 2008-01-08 Purdue Pharma, L.P. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US20040228917A1 (en) * 1991-12-24 2004-11-18 Purdue Pharma Lp Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US6129933A (en) * 1991-12-24 2000-10-10 Purdue Pharma Lp Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US20030180361A1 (en) * 1991-12-24 2003-09-25 Benjamin Oshlack Orally administrable opioid formulations having extended duration of effect
US5580578A (en) * 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5626872A (en) * 1992-06-16 1997-05-06 Roemmers S.A.I.C.F. Pharmaceutical soft capsules containing lysine clonixinate and a process for their preparation
US5641516A (en) * 1992-08-13 1997-06-24 Basf Aktiengesellschaft Compositions which contain active substances and are in the form of solid particles
US6193775B1 (en) * 1992-08-13 2001-02-27 Chisso Corporation Coated granular fertilizer
US20090117191A1 (en) * 1993-05-10 2009-05-07 Purdue Pharma Products L.P. Controlled release tramadol formulations
US7074430B2 (en) 1993-05-10 2006-07-11 Euro-Celtique S.A. Controlled release tramadol tramadol formulation
US6326027B1 (en) 1993-05-10 2001-12-04 Euro-Celtique S.A. Controlled release formulation
US6254887B1 (en) 1993-05-10 2001-07-03 Euro-Celtique S.A. Controlled release tramadol
US20060269603A1 (en) * 1993-05-10 2006-11-30 Euro-Celtique S.A. Controlled release tramadol formulations
US7740881B1 (en) 1993-07-01 2010-06-22 Purdue Pharma Lp Method of treating humans with opioid formulations having extended controlled release
US6143322A (en) * 1993-07-01 2000-11-07 Purdue Pharma L.P. Method of treating humans with opioid formulations having extended controlled release
US6103261A (en) * 1993-07-01 2000-08-15 Purdue Pharma Lp Opioid formulations having extended controlled release
US5879705A (en) * 1993-07-27 1999-03-09 Euro-Celtique S.A. Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
US6143328A (en) * 1993-07-27 2000-11-07 Euro-Celtique, S.A. Sustained release compositions and a method of preparing pharmaceutical compositions
US6048548A (en) * 1993-09-09 2000-04-11 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems-amorphous drugs
US6726930B1 (en) 1993-09-09 2004-04-27 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US20040241233A1 (en) * 1993-09-09 2004-12-02 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems- amorphous drugs
US5958456A (en) * 1993-09-09 1999-09-28 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US20040234598A1 (en) * 1993-09-09 2004-11-25 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US6136343A (en) * 1993-09-09 2000-10-24 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US20060105035A1 (en) * 1993-09-09 2006-05-18 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US6245356B1 (en) 1993-09-09 2001-06-12 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems-amorphous drugs
US5662933A (en) * 1993-09-09 1997-09-02 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US5965163A (en) * 1993-11-23 1999-10-12 Euro-Celtique, S.A. Substained release compositions and a method of preparing pharmaceutical compositions
US6162467A (en) * 1993-11-23 2000-12-19 Euro-Celtique, S.A. Sustained release compositions and a method of preparing pharmaceutical compositions
US5891471A (en) * 1993-11-23 1999-04-06 Euro-Celtique, S.A. Pharmaceutical multiparticulates
US5849240A (en) * 1993-11-23 1998-12-15 Euro-Celtique, S.A. Method of preparing sustained release pharmaceutical compositions
US5672360A (en) * 1993-11-23 1997-09-30 Purdue Pharma, L.P. Method of treating pain by administering 24 hour oral opioid formulations
US5843480A (en) * 1994-03-14 1998-12-01 Euro-Celtique, S.A. Controlled release diamorphine formulation
US20010038856A1 (en) * 1994-07-07 2001-11-08 Sonya Merrill Hydromorphone therapy
US20100028389A1 (en) * 1994-07-07 2010-02-04 Sonya Merrill Hydromorphone therapy
US6068855A (en) 1994-11-03 2000-05-30 Euro-Celtique S. A. Pharmaceutical composition containing a fusible carrier and method for producing the same
US20030190358A1 (en) * 1994-11-04 2003-10-09 Benjamin Oshlack Sustained release hydromorphone formulations exhibiting bimodal characteristics
US5902632A (en) * 1995-01-31 1999-05-11 Mehta; Atul M. Method of preparation of controlled release nifedipine formulations
US5945125A (en) * 1995-02-28 1999-08-31 Temple University Controlled release tablet
US5637319A (en) * 1995-03-01 1997-06-10 Takada; Kanji Controlled-release preparations
US6399096B1 (en) 1995-09-22 2002-06-04 Euro-Celtique S.A. Pharmaceutical formulation
US8506998B2 (en) 1995-09-22 2013-08-13 Euro-Celtique S.A. Pharmaceutical formulation
CN1104910C (en) * 1995-10-19 2003-04-09 昆士兰大学 Production of analgesic synergy by co-administration of sub-analgesic doses of a mu opioid agonist and kappa-2 opioid agonist
US5783212A (en) * 1996-02-02 1998-07-21 Temple University--of the Commonwealth System of Higher Education Controlled release drug delivery system
US6689386B2 (en) 1996-07-08 2004-02-10 Penwest Pharmaceuticals Co. Sustained release matrix for high-dose insoluble drugs
US6093420A (en) * 1996-07-08 2000-07-25 Edward Mendell Co., Inc. Sustained release matrix for high-dose insoluble drugs
US6245355B1 (en) 1996-07-08 2001-06-12 Edward Mendell Co., Inc. Sustained release matrix for high-dose insoluble drugs
US6190692B1 (en) 1997-01-29 2001-02-20 Cesare Busetti Time-specific controlled release capsule formulations and method of preparing same
US5891474A (en) * 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US6645527B2 (en) 1997-07-02 2003-11-11 Euro-Celtique S.A. Stabilized sustained release tramadol formulations
US6306438B1 (en) 1997-07-02 2001-10-23 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
US20020143028A1 (en) * 1997-09-17 2002-10-03 Burch Ronald M. Analgesic combination of oxycodone and nabumetone
US20020156091A1 (en) * 1997-09-17 2002-10-24 Burch Ronald M. Analgesic combination of oxycodone and nimesulide
US8168629B2 (en) 1997-09-17 2012-05-01 Purdue Pharma L.P. Analgesic combination of tramadol and meloxicam
US20020099049A1 (en) * 1997-09-17 2002-07-25 Burch Ronald M. Analgesic combination of oxycodone and meloxicam
US20080050427A1 (en) * 1997-09-17 2008-02-28 Purdue Pharma L.P. Analgesic combination of tramadol and meloxicam
US20020099064A1 (en) * 1997-09-17 2002-07-25 Burch Ronald M. Analgesic combination of oxycodone and T-614
US20070191412A1 (en) * 1997-09-17 2007-08-16 Burch Ronald M Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor
US8193209B2 (en) 1997-09-17 2012-06-05 Purdue Pharma L.P. Analgesic combination of oxycodone and meloxicam
US8685994B2 (en) 1997-09-17 2014-04-01 Purdue Pharma, L.P. Analgesic combination of oxycodone and celecoxib
US8143267B2 (en) 1997-09-17 2012-03-27 Purdue Pharma L.P. Analgesic combination of oxycodone and nimesulide
US8188107B2 (en) 1997-09-17 2012-05-29 Purdue Pharma L.P. Analgesic combination of oxycodone and N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide
US6875793B2 (en) 1997-10-15 2005-04-05 Penwest Pharmaceuticals Co. Once-a-day controlled release sulfonylurea formulation
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
US6537578B1 (en) 1997-10-15 2003-03-25 Penwest Pharmaceuticals Co. Once-a-day controlled release sulfonylurea formulation
US6066339A (en) * 1997-10-17 2000-05-23 Elan Corporation, Plc Oral morphine multiparticulate formulation
US20060141035A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-COA reductase inhibitor extended release formulation
US20060141036A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-CoA reductase inhibitor extended release formulation
US8679534B2 (en) 1997-12-12 2014-03-25 Andrx Labs, Llc HMG-CoA reductase inhibitor extended release formulation
US20040029962A1 (en) * 1997-12-12 2004-02-12 Chih-Ming Chen HMG-COA reductase inhibitor extended release formulation
US8105631B2 (en) 1997-12-22 2012-01-31 Purdue Pharma L.P. Opioid agonist/antagonist combinations
US9205082B2 (en) 1997-12-22 2015-12-08 Purdue Pharma L.P. Opioid agonist/antagonist combinations
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US8936808B1 (en) 1997-12-22 2015-01-20 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US7749542B2 (en) 1997-12-22 2010-07-06 Purdue Pharma Lp Opioid agonist/antagonist combinations
US6475494B2 (en) 1997-12-22 2002-11-05 Euro-Celtique S.A. Opioid agonist/antagonist combinations
EP1685839A1 (en) 1997-12-22 2006-08-02 Euro-Celtique S.A. Pharmaceutical oral dosage form comprising a combination of an opioid agonist and opioid antagonist
US6696066B2 (en) 1997-12-22 2004-02-24 Euro-Celtique S.A. Opioid agonist/antagonist combinations
US8932630B1 (en) 1997-12-22 2015-01-13 Purdue Pharma L.P Opioid agonist/antagonist combinations
US8673355B2 (en) 1997-12-22 2014-03-18 Purdue Pharma L.P. Opioid agonist/antagonist combinations
US9474750B2 (en) 1997-12-22 2016-10-25 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US7172767B2 (en) 1997-12-22 2007-02-06 Purdue Pharma L.P. Opioid agonist / antagonist combinations
US7419686B2 (en) 1997-12-22 2008-09-02 Purdue Pharma L.P. Opioid agonist/antagonist combinations
EP2266564A1 (en) 1997-12-22 2010-12-29 Euro-Celtique S.A. Pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist
US8822487B2 (en) 1997-12-22 2014-09-02 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US8524277B2 (en) 1998-03-06 2013-09-03 Alza Corporation Extended release dosage form
US20070128279A1 (en) * 1998-03-06 2007-06-07 Alza Corporation Extended Release Dosage Form
US6806294B2 (en) 1998-10-15 2004-10-19 Euro-Celtique S.A. Opioid analgesic
US20150313850A1 (en) * 1998-12-17 2015-11-05 Purdue Pharma Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
EP1967191A1 (en) 1998-12-17 2008-09-10 Euro-Celtique S.A. Controlled/modified release oral methylphenidate formulations
US9801823B2 (en) * 1998-12-17 2017-10-31 Rhodes Pharmaceuticals L.P. Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US9949931B2 (en) 1998-12-17 2018-04-24 Rhodes Pharmaceuticals L.P. Methods of treating attention deficit hyperactivity disorder
US10022330B2 (en) 1998-12-17 2018-07-17 Rhodes Pharmaceuticals L.P. Methods of preparing oral controlled release formulations
US10039719B2 (en) 1998-12-17 2018-08-07 Rhodes Pharmaceuticals L.P. Methods of treating attention deficit hyperactivity disorder
US10463624B2 (en) 1998-12-17 2019-11-05 Rhodes Pharmaceuticals L.P. Controlled release formulations
US6800329B2 (en) * 1999-02-12 2004-10-05 Lts Lohmann Therapie-Systeme Ag Method for producing film-type dosage
US6565877B1 (en) 1999-06-11 2003-05-20 Ranbaxy Laboratories Limited Taste masked compositions
US6555139B2 (en) 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
US8679535B2 (en) 1999-09-30 2014-03-25 Endo Pharmaceuticals Inc. Sustained release matrix systems for highly soluble drugs
US20040170684A1 (en) * 1999-09-30 2004-09-02 Penwest Pharmaceuticals Co. Sustained release matrix systems for highly soluble drugs
US20070218137A1 (en) * 1999-09-30 2007-09-20 Penwest Pharmaceuticals Co. Sustained release matrix systems for highly soluble drugs
US9675611B1 (en) 1999-10-29 2017-06-13 Purdue Pharma L.P. Methods of providing analgesia
EP1227798A1 (en) * 1999-10-29 2002-08-07 Euro-Celtique S.A. Controlled release hydrocodone formulations
US10076516B2 (en) 1999-10-29 2018-09-18 Purdue Pharma L.P. Methods of manufacturing oral dosage forms
EP1623703A1 (en) * 1999-10-29 2006-02-08 Euro-Celtique S.A. Controlled release hydrocodone formulations
US9056107B1 (en) 1999-10-29 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669024B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669022B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
EP2305218A1 (en) * 1999-10-29 2011-04-06 Euro-Celtique S.A. Controlled release hydrocodone formulations
US8980291B2 (en) 1999-10-29 2015-03-17 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9278074B2 (en) 1999-10-29 2016-03-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
EP2295043A1 (en) 1999-10-29 2011-03-16 Euro-Celtique S.A. Controlled release hydrocodone formulations
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US7943174B2 (en) 1999-10-29 2011-05-17 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9320717B2 (en) 1999-10-29 2016-04-26 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
EP2269587A1 (en) 1999-10-29 2011-01-05 Euro-Celtique S.A. Controlled release hydrocodone formulations
EP1227798A4 (en) * 1999-10-29 2004-06-30 Euro Celtique Sa Controlled release hydrocodone formulations
EP1935421A1 (en) 2000-02-08 2008-06-25 Euro-Celtique S.A. Controlled-release compositions containing opioid agonist and antagonist
US7658939B2 (en) 2000-02-08 2010-02-09 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US8936812B2 (en) 2000-02-08 2015-01-20 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US9456989B2 (en) 2000-02-08 2016-10-04 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
EP2277521A1 (en) 2000-02-08 2011-01-26 Euro-Celtique S.A. Tamper-resitant oral opioid agonist formulations
US9801828B2 (en) 2000-02-08 2017-10-31 Purdue Pharma L.P. Tamper resistant oral opioid agonist formulations
US7842309B2 (en) 2000-02-08 2010-11-30 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
EP2092936A2 (en) 2000-02-08 2009-08-26 Euro-Celtique S.A. Tamper-resistant oral opioid agonist formulations
US7842311B2 (en) 2000-02-08 2010-11-30 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
WO2001058447A1 (en) * 2000-02-08 2001-08-16 Euro-Celtique, S.A. Controlled-release compositions containing opioid agonist and antagonist
EP2283842A1 (en) 2000-02-08 2011-02-16 Euro-Celtique S.A. Tamper-resitant oral opioid agonist formulations
US10350173B2 (en) 2000-02-08 2019-07-16 Purdue Pharma L.P. Tamper resistant oral opioid agonist formulations
US8357399B2 (en) 2000-02-08 2013-01-22 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US8236351B2 (en) 2000-02-08 2012-08-07 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
EP2517710A1 (en) 2000-02-08 2012-10-31 Euro-Celtique S.A. Tamper-resistant oral opioid agonist formulations
EP3130338A1 (en) 2000-02-08 2017-02-15 Euro-Celtique S.A. Tamper-resistant oral opioid agonist formulations
US9278073B2 (en) 2000-02-08 2016-03-08 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US7682632B2 (en) 2000-02-08 2010-03-23 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US6716449B2 (en) 2000-02-08 2004-04-06 Euro-Celtique S.A. Controlled-release compositions containing opioid agonist and antagonist
US6696088B2 (en) 2000-02-08 2004-02-24 Euro-Celtique, S.A. Tamper-resistant oral opioid agonist formulations
US8586088B2 (en) 2000-02-08 2013-11-19 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US10588865B2 (en) 2000-02-08 2020-03-17 Purdue Pharma L.P. Tamper resistant oral opioid agonist formulations
US7718192B2 (en) 2000-02-08 2010-05-18 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US6635277B2 (en) 2000-04-12 2003-10-21 Wockhardt Limited Composition for pulsatile delivery of diltiazem and process of manufacture
US7514100B2 (en) 2000-10-30 2009-04-07 Purdue Pharma L.P. Controlled release hydrocodone formulations
EP2295042A1 (en) * 2000-10-30 2011-03-16 Euro-Celtique S.A. Controlled release hydrocodone formulations
EP1337244A4 (en) * 2000-10-30 2006-01-11 Euro Celtique Sa Controlled release hydrocodone formulations
EP2932964A1 (en) 2000-10-30 2015-10-21 Euro-Celtique S.A. Controlled release hydrocodone formulations
US8361499B2 (en) 2000-10-30 2013-01-29 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9198863B2 (en) 2000-10-30 2015-12-01 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9060940B2 (en) 2000-10-30 2015-06-23 Purdue Pharma L.P. Controlled release hydrocodone
EP1337244A1 (en) * 2000-10-30 2003-08-27 Euroceltique S.A. Controlled release hydrocodone formulations
US9056052B1 (en) 2000-10-30 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9205056B2 (en) 2000-10-30 2015-12-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9023401B1 (en) 2000-10-30 2015-05-05 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9205055B2 (en) 2000-10-30 2015-12-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9289391B2 (en) 2000-10-30 2016-03-22 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8231898B2 (en) 2000-10-30 2012-07-31 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8647667B2 (en) 2000-10-30 2014-02-11 Purdue Pharma, L.P. Controlled release hydrocodone formulations
US9669023B2 (en) 2000-10-30 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8551520B2 (en) 2000-10-30 2013-10-08 Purdue Pharma L.P. Controlled release hydrocodone
US20040047907A1 (en) * 2000-10-30 2004-03-11 Benjamin Oshlack Controlled release hydrocodone formulations
US9572804B2 (en) 2000-10-30 2017-02-21 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9572805B2 (en) 2000-10-30 2017-02-21 Purdue Pharma L.P. Controlled release hydrocodone formulations
EP2263658A1 (en) * 2000-10-30 2010-12-22 Euro-Celtique S.A. Controlled release hydrocodone formulations
US9682077B2 (en) 2000-10-30 2017-06-20 Purdue Pharma L.P. Methods of providing analgesia
US6733783B2 (en) 2000-10-30 2004-05-11 Euro-Celtique S.A. Controlled release hydrocodone formulations
US8142811B2 (en) 2000-10-30 2012-03-27 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9504681B2 (en) 2000-10-30 2016-11-29 Purdue Pharma L.P. Controlled release hydrocodone formulations
EP2283829A1 (en) * 2000-10-30 2011-02-16 Euro-Celtique S.A. Controlled release hydrocodone formulations
US9517236B2 (en) 2000-10-30 2016-12-13 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10022368B2 (en) 2000-10-30 2018-07-17 Purdue Pharma L.P. Methods of manufacturing oral formulations
US9526724B2 (en) 2000-10-30 2016-12-27 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8715721B2 (en) 2000-10-30 2014-05-06 Purdue Pharma L.P. Controlled release hydrocodone
US9750736B2 (en) 2001-05-02 2017-09-05 Purdue Pharma L.P. Oxycodone formulations
EP2011485A2 (en) 2001-05-02 2009-01-07 Euro-Celtique S.A. Once-a-day oxycodone formulations
US7846476B2 (en) 2001-05-02 2010-12-07 Purdue Pharma L.P. Once-a-day oxycodone formulations
EP3146963A1 (en) 2001-05-02 2017-03-29 Euro-Celtique S.A. Once-a-day oxycodone formulations
US9655893B2 (en) 2001-05-02 2017-05-23 Purdue Pharma L.P. Once-a-day oxycodone formulations
US10660886B2 (en) 2001-05-02 2020-05-26 Purdue Pharma L.P. Oxycodone formulations
US9655894B2 (en) 2001-05-02 2017-05-23 Purdue Pharma L.P. Once-A day oxycodone formulations
US9358230B1 (en) 2001-05-11 2016-06-07 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9168252B2 (en) 2001-05-11 2015-10-27 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US8969369B2 (en) 2001-05-11 2015-03-03 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9511066B2 (en) 2001-05-11 2016-12-06 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9056051B2 (en) 2001-05-11 2015-06-16 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9084729B2 (en) 2001-05-11 2015-07-21 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9161937B2 (en) 2001-05-11 2015-10-20 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9480685B2 (en) 2001-05-11 2016-11-01 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9283216B2 (en) 2001-05-11 2016-03-15 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9283221B2 (en) 2001-05-11 2016-03-15 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9345701B1 (en) 2001-05-11 2016-05-24 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US7052706B2 (en) 2001-06-08 2006-05-30 Nostrum Pharmaceuticals, Inc. Control release formulation containing a hydrophobic material as the sustained release agent
US20030077324A1 (en) * 2001-06-08 2003-04-24 Nostrum Pharmaceuticals, Inc. Control release formulation containing a hydrophobic material as the sustained release agent
US20060204573A1 (en) * 2001-06-08 2006-09-14 Nostrum Pharmaceuticals, Inc. Control release formulation containing a hydrophobic material as the sustained release agent
US8545882B2 (en) 2001-06-08 2013-10-01 Nostrum Pharmaceuticals, Inc. Control release formulation containing a hydrophobic material as the sustained release agent
US7943173B2 (en) 2001-07-18 2011-05-17 Purdue Pharma L.P. Pharmaceutical combinations of oxycodone and naloxone
US9757341B2 (en) 2001-08-06 2017-09-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9034376B2 (en) 2001-08-06 2015-05-19 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8609683B2 (en) 2001-08-06 2013-12-17 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9308170B2 (en) 2001-08-06 2016-04-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9861582B2 (en) 2001-08-06 2018-01-09 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9867784B2 (en) 2001-08-06 2018-01-16 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
USRE45822E1 (en) 2001-08-06 2015-12-22 Purdue Pharma L.P. Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US9867783B2 (en) 2001-08-06 2018-01-16 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8815287B2 (en) 2001-08-06 2014-08-26 Purdue Pharma L.P. Opiod agonist formulations with releasable and sequestered antagonist
US9308171B2 (en) 2001-08-06 2016-04-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8231901B2 (en) 2001-08-06 2012-07-31 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US9872836B2 (en) 2001-08-06 2018-01-23 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10064825B2 (en) 2001-08-06 2018-09-04 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9877924B2 (en) 2001-08-06 2018-01-30 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9693961B2 (en) 2001-08-06 2017-07-04 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8337888B2 (en) 2001-08-06 2012-12-25 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8999961B2 (en) 2001-08-06 2015-04-07 Purdue Pharma, L.P. Pharmaceutical formulation containing gelling agent
US9387173B2 (en) 2001-08-06 2016-07-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9387174B2 (en) 2001-08-06 2016-07-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8758825B2 (en) 2001-08-06 2014-06-24 Purdue Pharma L.P. Sequestered antagonist formulations
US8389007B2 (en) 2001-08-06 2013-03-05 Purdue Pharma L.P. Pharmaceutical composition containing gelling agent
US7384653B2 (en) 2001-08-06 2008-06-10 Purdue Pharma L.P. Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US10076497B2 (en) 2001-08-06 2018-09-18 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9040084B2 (en) 2001-08-06 2015-05-26 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9044435B2 (en) 2001-08-06 2015-06-02 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8465774B2 (en) 2001-08-06 2013-06-18 Purdue Pharma L.P. Sequestered antagonist formulations
US9861583B2 (en) 2001-08-06 2018-01-09 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8871265B2 (en) 2001-08-06 2014-10-28 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US7914818B2 (en) 2001-08-06 2011-03-29 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US9517207B2 (en) 2001-08-06 2016-12-13 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9949930B2 (en) 2001-08-06 2018-04-24 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US8518443B2 (en) 2001-08-06 2013-08-27 Purdue Pharma, L.P. Opioid agonist formulations with releasable and sequestered antagonist
US9968559B2 (en) 2001-08-06 2018-05-15 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9060976B2 (en) 2001-08-06 2015-06-23 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US8529948B1 (en) 2001-08-06 2013-09-10 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10500160B2 (en) 2001-08-06 2019-12-10 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10064824B2 (en) 2001-08-06 2018-09-04 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10071057B2 (en) 2001-08-06 2018-09-11 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US11135171B2 (en) 2001-08-06 2021-10-05 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US20030099711A1 (en) * 2001-08-29 2003-05-29 David Meadows Sustained release preparations
KR100540035B1 (en) * 2002-02-01 2005-12-29 주식회사 태평양 Multi-stage oral drug controlled-release system
WO2003063834A1 (en) * 2002-02-01 2003-08-07 Pacific Corporation Multi-stage oral drug controlled-release system
US8362062B2 (en) 2002-02-15 2013-01-29 Mcneil-Ppc, Inc. Pharmaceutical compositions with improved dissolution
US20090088443A1 (en) * 2002-02-15 2009-04-02 Julius Remenar Novel crystalline forms of conazoles and methods of making and using the same
US20070026078A1 (en) * 2002-02-15 2007-02-01 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US10633344B2 (en) 2002-03-01 2020-04-28 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
US8173199B2 (en) * 2002-03-27 2012-05-08 Advanced Cardiovascular Systems, Inc. 40-O-(2-hydroxy)ethyl-rapamycin coated stent
US8961588B2 (en) 2002-03-27 2015-02-24 Advanced Cardiovascular Systems, Inc. Method of coating a stent with a release polymer for 40-O-(2-hydroxy)ethyl-rapamycin
US9907793B2 (en) 2002-04-05 2018-03-06 Purdue Pharma L.P. Pharmaceutical preparation containing oxycodone and naloxone
US9655855B2 (en) 2002-04-05 2017-05-23 Purdue Pharma L.P. Matrix for sustained, invariant and independent release of active compounds
US8846090B2 (en) 2002-04-05 2014-09-30 Euro-Celtique S.A. Matrix for sustained, invariant and independent release of active compounds
US10420762B2 (en) 2002-04-05 2019-09-24 Purdue Pharma L.P. Pharmaceutical preparation containing oxycodone and naloxone
US9555000B2 (en) 2002-04-05 2017-01-31 Purdue Pharma L.P. Pharmaceutical preparation containing oxycodone and naloxone
US20050245483A1 (en) * 2002-04-05 2005-11-03 Bianca Brogmann Matrix for sustained, invariant and independent release of active compounds
US8846091B2 (en) 2002-04-05 2014-09-30 Euro-Celtique S.A. Matrix for sustained, invariant and independent release of active compounds
US20050245556A1 (en) * 2002-04-05 2005-11-03 Bianca Brogmann Pharmaceutical preparation containing oxycodone and naloxone
US10525053B2 (en) 2002-07-05 2020-01-07 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
EP1894562A1 (en) 2002-08-15 2008-03-05 Euro-Celtique S.A. Pharmaceutical compositions
US8685444B2 (en) 2002-09-20 2014-04-01 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and methods
US8685443B2 (en) 2002-09-20 2014-04-01 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and methods
US20060052432A1 (en) * 2002-09-20 2006-03-09 Julius Remenar Pharmaceutical compositions with improved dissolution
US8487002B2 (en) 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
US7988998B2 (en) 2002-10-25 2011-08-02 Labopharm Inc. Sustained-release tramadol formulations with 24-hour efficacy
US20060148877A1 (en) * 2002-11-26 2006-07-06 Transform Pharmaceuticals, Inc. Pharmaceutical formulations of celcoxib
US9233160B2 (en) 2002-12-13 2016-01-12 Durect Corporation Oral drug delivery system
US9517271B2 (en) 2002-12-13 2016-12-13 Durect Corporation Oral drug delivery system
US8354124B2 (en) 2002-12-13 2013-01-15 Durect Corporation Oral drug delivery system
US9918982B2 (en) 2002-12-13 2018-03-20 Durect Corporation Oral drug delivery system
US8420120B2 (en) 2002-12-13 2013-04-16 Durect Corporation Oral drug delivery system
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
US8492423B2 (en) 2002-12-30 2013-07-23 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
EP2339328A2 (en) 2002-12-30 2011-06-29 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of celecoxib
US8425933B2 (en) 2003-04-08 2013-04-23 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US8703186B2 (en) 2003-04-08 2014-04-22 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US8182836B2 (en) 2003-04-08 2012-05-22 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US10092519B2 (en) 2003-04-21 2018-10-09 Purdue Pharma L.P. Pharmaceutical products
WO2004093801A2 (en) 2003-04-21 2004-11-04 Euro-Celtique S.A. Pharmaceutical products
EP3150228A2 (en) 2003-04-21 2017-04-05 Euro-Celtique S.A. Tamper-resistant products for opioid delivery
EP2179724A2 (en) 2003-04-21 2010-04-28 Euro-Celtique S.A. Tamper-resistant products for opioid delivery
EP2258347A2 (en) 2003-04-21 2010-12-08 Euro-Celtique S.A. Tamper-resistant products for opioid delivery
EP2269579A2 (en) 2003-04-21 2011-01-05 Euro-Celtique S.A. Tamper-resistant products for opioid delivery
US9149436B2 (en) 2003-04-21 2015-10-06 Purdue Pharma L.P. Pharmaceutical product comprising a sequestered agent
EP2298303A1 (en) 2003-09-25 2011-03-23 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
EP2184058A1 (en) 2003-09-26 2010-05-12 Alza Corporation Drug coating providing high drug loading and methods for providing the same
US8246986B2 (en) 2003-09-26 2012-08-21 Alza Corporation Drug coating providing high drug loading
US8226979B2 (en) 2003-09-26 2012-07-24 Alza Corporation Drug coating providing high drug loading and methods for providing the same
US20070259033A1 (en) * 2003-09-26 2007-11-08 Evangeline Cruz Controlled release formulations exhibiting an ascending rate of release
US20050084540A1 (en) * 2003-10-17 2005-04-21 Indranil Nandi Taste masking antibiotic composition
US8709476B2 (en) 2003-11-04 2014-04-29 Supernus Pharmaceuticals, Inc. Compositions of quaternary ammonium compounds containing bioavailability enhancers
US20050191351A1 (en) * 2003-11-04 2005-09-01 Shire Laboratories, Inc. Once daily dosage forms of trospium
US20080207661A1 (en) * 2003-11-04 2008-08-28 Supernus Pharmaceuticals, Inc. Once daily dosage forms of trospium
US20100221352A1 (en) * 2003-11-04 2010-09-02 Supernus Pharmaceuticals, Inc. Pharmaceutical composition for the once-a-day oral administration of trospium chloride
US20080207662A1 (en) * 2003-11-04 2008-08-28 Supernus Pharmaceuticals, Inc. Once daily dosage forms of trospium
US20100221353A1 (en) * 2003-11-04 2010-09-02 Supernus Pharmaceuticals, Inc. Pharmaceutical Composition For Once-A-Day Administration of Trospium Chloride
US20080207663A1 (en) * 2003-11-04 2008-08-28 Supernus Pharmaceuticals, Inc. Once daily dosage forms of trospium
US7410978B2 (en) 2003-11-04 2008-08-12 Supernus Pharmaceuticals, Inc. Once daily dosage forms of trospium
US7763635B2 (en) 2003-11-04 2010-07-27 Supermus Pharmaceuticals, Inc. Once daily dosage forms of trospium
US7781449B2 (en) 2003-11-04 2010-08-24 Supernus Pharmaceuticals, Inc. Trospium chloride treatment method
US20100221354A1 (en) * 2003-11-04 2010-09-02 Supernus Pharmaceuticals, Inc. Pharmaceutical composition for once-a-day oral administration of trospium chloride
US20100222375A1 (en) * 2003-11-04 2010-09-02 Supernus Pharmaceuticals, Inc. Pharmaceutical Composition Comprising Trospium Chloride for Once-A-Day Administration
US20100221355A1 (en) * 2003-11-04 2010-09-02 Supernus Pharmaceuticals, Inc. Pharmaceutical composition for once-a-day oral administration of trospium chloride
US7781448B2 (en) 2003-11-04 2010-08-24 Supernus Pharmaceuticals, Inc. Once daily dosage forms of trospium
US7759359B2 (en) 2003-11-04 2010-07-20 Supernus Pharmaceuticals, Inc. Method of treating bladder dysfunction with once-a-day trospium salt formulation
EP2343073A2 (en) 2003-12-11 2011-07-13 Sepracor Inc. Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
WO2005060968A1 (en) 2003-12-11 2005-07-07 Sepracor Inc. Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US11384091B2 (en) 2004-03-30 2022-07-12 Purdue Pharma L.P. Process for preparing oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US20090227615A1 (en) * 2004-03-30 2009-09-10 Purdue Pharma Lp Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US10689389B2 (en) 2004-03-30 2020-06-23 Purdue Pharma L.P. Process for preparing oxycodone compositions
US9777011B2 (en) 2004-03-30 2017-10-03 Purdue Pharma L.P. Process for preparing oxycodone compositions
US7129248B2 (en) 2004-03-30 2006-10-31 Euro-Celtique, S.A. Process for preparing oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US20070117831A1 (en) * 2004-03-30 2007-05-24 Euro-Celtique S.A. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US20070117830A1 (en) * 2004-03-30 2007-05-24 Euro-Celtique S.A. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US20070117829A1 (en) * 2004-03-30 2007-05-24 Euro-Celtique S.A. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US20070179169A1 (en) * 2004-03-30 2007-08-02 Euro-Celtique S.A. Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
US10407434B2 (en) 2004-03-30 2019-09-10 Purdue Pharma L.P. Process for preparing oxycodone compositions
EP2305683A1 (en) 2004-03-30 2011-04-06 Euro-Celtique S.A. Pharmaceutical dosage form comprising oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
EP2311839A1 (en) 2004-03-30 2011-04-20 Euro-Celtique S.A. Oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone
US9073933B2 (en) 2004-03-30 2015-07-07 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
US10696684B2 (en) 2004-03-30 2020-06-30 Purdue Pharma L.P. Process for preparing oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
EP2314589A1 (en) 2004-03-30 2011-04-27 Euro-Celtique S.A. Process for preparing oxycodone hydrochloride having less than 25ppm 14-hydroxycodeinone
US9522919B2 (en) 2004-03-30 2016-12-20 Purdue Pharma L.P. Oxycodone compositions
US20100152449A1 (en) * 2004-03-30 2010-06-17 Purdue Pharma Lp 8a,14-DIHYDROXY-7,8-DIHYDROCODEINONE
EP2426132A1 (en) 2004-03-30 2012-03-07 Euro-Celtique S.A. Process for preparing 14-hydroxycodeinone from thebaine
US20060173029A1 (en) * 2004-03-30 2006-08-03 Euro-Celtique S.A. Oxycodone hydrochloride having less than 25 ppm 14- hydroxycodeinone
US11236098B2 (en) 2004-03-30 2022-02-01 Purdue Pharma L.P. Process for preparing oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US10259819B2 (en) 2004-03-30 2019-04-16 Purdue Pharma L.P. Process for preparing oxycodone compositions
US7683072B2 (en) 2004-03-30 2010-03-23 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US8822687B2 (en) 2004-03-30 2014-09-02 Purdue Pharma L.P. 8a,14-dihydroxy-7,8-dihydrocodeinone
US7674800B2 (en) 2004-03-30 2010-03-09 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
US7674799B2 (en) 2004-03-30 2010-03-09 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
EP2319846A1 (en) 2004-03-30 2011-05-11 Euro-Celtique S.A. Process for preparing oxycodone hydrochloride having less than 25ppm 14-hydroxycodeinone
US7674798B2 (en) 2004-03-30 2010-03-09 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
EP2316837A1 (en) 2004-03-30 2011-05-04 Euro-Celtique S.A. Process for preparing oxycodone hydrochloride having less than 25ppm 14-hydroxycodeinone
US20110104214A1 (en) * 2004-04-15 2011-05-05 Purdue Pharma L.P. Once-a-day oxycodone formulations
US8518925B2 (en) 2004-06-08 2013-08-27 Euro-Celtique S.A. Opioids for the treatment of the chronic obstructive pulmonary disease (COPD)
EP1961421A1 (en) 2004-06-08 2008-08-27 Euro-Celtique S.A. Opioids for the treatment of the chronic obstructive pulmonary disease (COPD)
EP2255808A2 (en) 2004-06-08 2010-12-01 Euro-Celtique S.A. Opioids for the treatment of the restlessness of the lower limbs
US10525052B2 (en) 2004-06-12 2020-01-07 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US9034377B2 (en) 2004-09-01 2015-05-19 Purdue Pharma, L.P. Opioid dosage forms having dose proportional steady state Cave and AUC and less than dose proportional single dose Cmax
US9326959B2 (en) 2004-09-01 2016-05-03 Purdue Pharma, L.P. Opioid dosage forms having dose proportional steady state Cave and AUC and less than dose proportional single dose Cmax
US20080132532A1 (en) * 2004-09-01 2008-06-05 Curtis Wright Opioid Dosage Forms Having Dose Proportional Steady State Cave and Auc and Less Than Dose Proportional Single Dose Cmax
US8541026B2 (en) 2004-09-24 2013-09-24 Abbvie Inc. Sustained release formulations of opioid and nonopioid analgesics
US20070259045A1 (en) * 2005-01-28 2007-11-08 Euro-Celtique S.A. Alcohol Resistant Dosage Forms
US20110172259A1 (en) * 2005-02-28 2011-07-14 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
US10258235B2 (en) 2005-02-28 2019-04-16 Purdue Pharma L.P. Method and device for the assessment of bowel function
US8962019B2 (en) 2005-09-09 2015-02-24 Angelini Pharma, Inc. Sustained drug release composition
US8795723B2 (en) 2005-09-09 2014-08-05 Angelini Pharma Inc. Sustained drug release compositions
US8414919B2 (en) 2005-09-09 2013-04-09 Angelini Labopharm, Llc Sustained drug release composition
US9439866B2 (en) 2005-09-09 2016-09-13 Angelini Pharma, Inc. Trazodone composition for once a day administration
US7829120B2 (en) 2005-09-09 2010-11-09 Labopharm Inc. Trazodone composition for once a day administration
US20090169626A1 (en) * 2006-01-27 2009-07-02 Euro-Celtique S.A. Tamper resistant dosage forms
US20070184198A1 (en) * 2006-02-07 2007-08-09 Fmc Corporation Coating process to produce controlled release coatings
US7829148B2 (en) 2006-02-07 2010-11-09 Fmc Corporation Coating process to produce controlled release coatings
US9198864B2 (en) 2006-03-16 2015-12-01 Tris Pharma, Inc Modified release formulations containing drug-ion exchange resin complexes
US9522191B2 (en) 2006-03-16 2016-12-20 Tris Pharma, Inc. Modified release formulations containing drug—ion exchange resin complexes
US8597684B2 (en) 2006-03-16 2013-12-03 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8202537B2 (en) 2006-03-16 2012-06-19 Tris Pharma Inc Modified release formulations containing drug-ion exchange resin complexes
US8062667B2 (en) 2006-03-16 2011-11-22 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8337890B2 (en) 2006-03-16 2012-12-25 Tris Pharma Inc Modified release formulations containing drug-ion exchange resin complexes
US9675703B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc Modified release formulations containing drug - ion exchange resin complexes
US9675704B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8883217B2 (en) 2006-03-16 2014-11-11 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8747902B2 (en) 2006-03-16 2014-06-10 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8790700B2 (en) 2006-03-16 2014-07-29 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US10086087B2 (en) 2006-03-16 2018-10-02 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US10933143B2 (en) 2006-03-16 2021-03-02 Tris Pharma, Inc Modified release formulations containing drug-ion exchange resin complexes
US10172958B2 (en) 2006-03-16 2019-01-08 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US10668163B2 (en) 2006-03-16 2020-06-02 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8491935B2 (en) 2006-03-16 2013-07-23 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US20100166858A1 (en) * 2006-03-16 2010-07-01 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US20070215511A1 (en) * 2006-03-16 2007-09-20 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US9549989B2 (en) 2006-03-16 2017-01-24 Tris Pharma, Inc Modified release formulations containing drug-ion exchange resin complexes
US8642078B2 (en) * 2006-03-31 2014-02-04 Lek Pharmaceuticals, D.D. Coated formulations for tolterodine
US20090214642A1 (en) * 2006-03-31 2009-08-27 Lek Pharmaceuticals D.D. Coated formulations for tolterodine
US8877247B2 (en) 2006-06-19 2014-11-04 Alpharma Pharmaceuticals Llc Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist
US8846104B2 (en) 2006-06-19 2014-09-30 Alpharma Pharmaceuticals Llc Pharmaceutical compositions for the deterrence and/or prevention of abuse
US7682634B2 (en) 2006-06-19 2010-03-23 Alpharma Pharmaceuticals, Llc Pharmaceutical compositions
US8158156B2 (en) 2006-06-19 2012-04-17 Alpharma Pharmaceuticals, Llc Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist
US7682633B2 (en) 2006-06-19 2010-03-23 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
US9545380B2 (en) 2006-08-25 2017-01-17 Purdue Pharma L.P. Tamper resistant dosage forms
US9770417B2 (en) 2006-08-25 2017-09-26 Purdue Pharma L.P. Tamper resistant dosage forms
US9486412B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US8821929B2 (en) 2006-08-25 2014-09-02 Purdue Pharma L.P. Tamper resistant dosage forms
US8834925B2 (en) 2006-08-25 2014-09-16 Purdue Pharma L.P. Tamper resistant dosage forms
US9492391B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9084816B2 (en) 2006-08-25 2015-07-21 Purdue Pharma L.P. Tamper resistant dosage forms
US11304909B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11298322B2 (en) 2006-08-25 2022-04-12 Purdue Pharma L.P. Tamper resistant dosage forms
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US8846086B2 (en) 2006-08-25 2014-09-30 Purdue Pharma L.P. Tamper resistant dosage forms
US9775811B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US10076498B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US9486413B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US9775809B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US10076499B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US8894987B2 (en) 2006-08-25 2014-11-25 William H. McKenna Tamper resistant dosage forms
US8894988B2 (en) 2006-08-25 2014-11-25 Purdue Pharma L.P. Tamper resistant dosage forms
US9101661B2 (en) 2006-08-25 2015-08-11 Purdue Pharma L.P. Tamper resistant dosage forms
US9492392B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9492393B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9095614B2 (en) 2006-08-25 2015-08-04 Purdue Pharma L.P. Tamper resistant dosage forms
US9492389B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US11826472B2 (en) 2006-08-25 2023-11-28 Purdue Pharma L.P. Tamper resistant dosage forms
US11904055B2 (en) 2006-08-25 2024-02-20 Purdue Pharma L.P. Tamper resistant dosage forms
US9492390B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US11938225B2 (en) 2006-08-25 2024-03-26 Purdue Pharm L.P. Tamper resistant dosage forms
US9095615B2 (en) 2006-08-25 2015-08-04 Purdue Pharma L.P. Tamper resistant dosage forms
US9763933B2 (en) 2006-08-25 2017-09-19 Purdue Pharma L.P. Tamper resistant dosage forms
US9763886B2 (en) 2006-08-25 2017-09-19 Purdue Pharma L.P. Tamper resistant dosage forms
US9770416B2 (en) 2006-08-25 2017-09-26 Purdue Pharma L.P. Tamper resistant dosage forms
US11304908B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US9775810B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775812B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775808B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US8911719B2 (en) 2006-08-25 2014-12-16 Purdue Pharma Lp Tamper resistant dosage forms
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
US9216176B2 (en) 2006-09-15 2015-12-22 Cima Labs Inc. Abuse resistant drug formulation
US9572803B2 (en) 2006-09-15 2017-02-21 Cima Labs Inc. Abuse resistant drug formulation
US20080146601A1 (en) * 2006-12-14 2008-06-19 Johnson Matthey Public Limited Company Method for making analgesics
US7851482B2 (en) 2006-12-14 2010-12-14 Johnson Matthey Public Limited Compnay Method for making analgesics
US20150064245A1 (en) * 2007-08-13 2015-03-05 lnspirion Delivery Technologies, LLC Abuse Resistant Forms of Immediate Release Hydromorphone, Method of Use and Method of Making
US11191730B2 (en) * 2007-08-13 2021-12-07 Ohemo Life Sciences Inc. Abuse resistant forms of immediate release hydromorphone, method of use and method of making
US11291634B2 (en) * 2007-08-13 2022-04-05 OHEMO Life Sciences, Inc. Abuse resistant forms of extended release oxymorphone, method of use and method of making
US11285112B2 (en) * 2007-08-13 2022-03-29 Oheno Life Sciences, Inc Abuse resistant forms of immediate release oxymorphone, method of use and method of making
US11278500B2 (en) * 2007-08-13 2022-03-22 OHEMO Life Sciences, Inc. Abuse resistant forms of extended release hydrocodone, method of use and method of making
US20150071998A1 (en) * 2007-08-13 2015-03-12 Inspirion Delivery Technologies, Llc Abuse resistant forms of immediate release oxymorphone, method of use and method of making
US20150064248A1 (en) * 2007-08-13 2015-03-05 Inspirion Delivery Technologies, Llc Abuse resistant forms of extended release hydromorphone, method of use and method of making
US20150071995A1 (en) * 2007-08-13 2015-03-12 Inspirion Delivery Technologies, Llc Abuse resistant forms of extended release hydrocodone, method of use and method of making
US20150064247A1 (en) * 2007-08-13 2015-03-05 Inspirion Delivery Technologies, Llc Abuse resistant forms of immediate release hydrocodone, method of use and method of making
US20150064246A1 (en) * 2007-08-13 2015-03-05 Inspirion Delivery Technologies, Llc Abuse resistant forms of extended release oxymorphone, method of use and method of making
US10206883B2 (en) 2007-12-06 2019-02-19 Durect Corporation Oral pharamaceutical dosage forms
US9592204B2 (en) 2007-12-06 2017-03-14 Durect Corporation Oral pharmaceutical dosage forms
US9655861B2 (en) 2007-12-06 2017-05-23 Durect Corporation Oral pharmaceutical dosage forms
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
WO2010036777A1 (en) 2008-09-25 2010-04-01 Isp Investments Inc. Smooth, high solids tablet coating composition
US9884056B2 (en) 2008-11-03 2018-02-06 Durect Corporation Oral pharmaceutical dosage forms
US9616055B2 (en) 2008-11-03 2017-04-11 Durect Corporation Oral pharmaceutical dosage forms
US10328068B2 (en) 2008-11-03 2019-06-25 Durect Corporation Oral pharmaceutical dosage forms
US9820983B2 (en) 2009-03-10 2017-11-21 Purdue Pharma L.P. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
US9271940B2 (en) 2009-03-10 2016-03-01 Purdue Pharma L.P. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US20110223244A1 (en) * 2010-03-09 2011-09-15 Elan Pharma International Limited Alcohol resistant enteric pharmaceutical compositions
WO2011112709A1 (en) 2010-03-09 2011-09-15 Elan Pharma International Limited Alcohol resistant enteric pharmaceutical compositions
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US8623409B1 (en) 2010-10-20 2014-01-07 Tris Pharma Inc. Clonidine formulation
WO2012080833A2 (en) 2010-12-13 2012-06-21 Purdue Pharma L.P. Controlled release dosage forms
US20160158158A1 (en) 2010-12-22 2016-06-09 Purdue Pharma L.P. Encased Tamper Resistant Controlled Release Dosage Forms
US9572779B2 (en) 2010-12-22 2017-02-21 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9861584B2 (en) 2010-12-22 2018-01-09 Purdue Pharma L.P. Tamper resistant controlled release dosage forms
US11911512B2 (en) 2010-12-22 2024-02-27 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US10966932B2 (en) 2010-12-22 2021-04-06 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9750703B2 (en) 2010-12-22 2017-09-05 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US8808740B2 (en) 2010-12-22 2014-08-19 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9393206B2 (en) 2010-12-22 2016-07-19 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US11590082B2 (en) 2010-12-22 2023-02-28 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9744136B2 (en) 2010-12-22 2017-08-29 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9872837B2 (en) 2010-12-22 2018-01-23 Purdue Pharma L.P. Tamper resistant controlled release dosage forms
US9233073B2 (en) 2010-12-23 2016-01-12 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US9707180B2 (en) 2010-12-23 2017-07-18 Purdue Pharma L.P. Methods of preparing tamper resistant solid oral dosage forms
US9895317B2 (en) 2010-12-23 2018-02-20 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
EP2606880A1 (en) * 2011-12-23 2013-06-26 LEK Pharmaceuticals d.d. Coating process with aqueous latex coating
US9872856B2 (en) 2012-04-17 2018-01-23 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US9931337B2 (en) 2012-04-17 2018-04-03 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US10398690B2 (en) 2012-04-17 2019-09-03 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US9867817B2 (en) 2012-04-17 2018-01-16 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US9662326B2 (en) 2012-04-17 2017-05-30 Purdue Pharma L.P. Systems for treating an opioid-induced adverse pharmacodynamic response
US9884059B2 (en) 2012-04-17 2018-02-06 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US9855262B2 (en) 2012-04-17 2018-01-02 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US10525010B2 (en) 2012-05-02 2020-01-07 Capsugel Belgium Nv Aqueous dispersions of controlled release polymers and shells and capsules thereof
WO2013164122A1 (en) * 2012-05-02 2013-11-07 Capsugel France SAS Aqueous dispersions of controlled release polymers and shells and capsules thereof
US10316042B2 (en) 2012-07-16 2019-06-11 Rhodes Technologies Process for improved opioid synthesis
US10202396B2 (en) 2012-07-16 2019-02-12 Rhodes Technologies Process for improved opioid synthesis
US11390627B2 (en) 2012-07-16 2022-07-19 Rhodes Technologies Process for improved opioid synthesis
WO2014013313A1 (en) 2012-07-16 2014-01-23 Rhodes Technologies Process for improved opioid synthesis
WO2014013311A1 (en) 2012-07-16 2014-01-23 Rhodes Technologies Process for improved opioid synthesis
US9655971B2 (en) 2013-02-05 2017-05-23 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10478504B2 (en) 2013-02-05 2019-11-19 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9545448B2 (en) 2013-02-05 2017-01-17 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9662399B2 (en) 2013-02-05 2017-05-30 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US11576974B2 (en) 2013-02-05 2023-02-14 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9579389B2 (en) 2013-02-05 2017-02-28 Purdue Pharma L.P. Methods of preparing tamper resistant pharmaceutical formulations
US10792364B2 (en) 2013-02-05 2020-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9149533B2 (en) 2013-02-05 2015-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10517832B2 (en) 2013-03-15 2019-12-31 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9555113B2 (en) 2013-03-15 2017-01-31 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US10195152B2 (en) 2013-03-15 2019-02-05 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9616030B2 (en) 2013-03-15 2017-04-11 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10300142B2 (en) 2013-03-15 2019-05-28 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US9572885B2 (en) 2013-03-15 2017-02-21 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9907851B2 (en) 2013-03-15 2018-03-06 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US9855333B2 (en) 2013-03-15 2018-01-02 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
US10071089B2 (en) 2013-07-23 2018-09-11 Euro-Celtique S.A. Combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation
US9120800B2 (en) 2013-08-02 2015-09-01 Johnson Matthey Public Limited Company Process for the preparation of oxymorphone alkaloid and oxymorphone salts
US10813886B2 (en) 2013-11-04 2020-10-27 Capsugel Belgium Nv Methods and systems for improved bioavailability of active pharmaceutical ingredients including esomeprazole
WO2015107471A1 (en) 2014-01-15 2015-07-23 Rhodes Technologies Process for improved oxycodone synthesis
US10844072B2 (en) 2014-01-15 2020-11-24 Rhodes Technologies Process for improved oxycodone synthesis
US10428079B2 (en) 2014-01-15 2019-10-01 Rhodes Technologies Process for improved oxycodone synthesis
US9938285B2 (en) 2014-01-15 2018-04-10 Rhodes Technologies Process for improved oxymorphone synthesis
US10189852B2 (en) 2014-01-15 2019-01-29 Rhodes Technologies Process for improved oxymorphone synthesis
WO2015107472A1 (en) 2014-01-15 2015-07-23 Rhodes Technologies Process for improved oxymorphone synthesis
US9932348B2 (en) 2014-01-15 2018-04-03 Rhodes Technologies Process for improved oxycodone synthesis
WO2015138200A1 (en) 2014-03-11 2015-09-17 Fmc Corporation Controlled release composition and method
CN106102723A (en) * 2014-03-11 2016-11-09 Fmc有限公司 Controlled release composition and method
WO2015143253A1 (en) 2014-03-21 2015-09-24 Johnson Matthey Public Limited Company Crystalle forms of oxymorphone hydrochloride
US9062063B1 (en) 2014-03-21 2015-06-23 Johnson Matthey Public Limited Company Forms of oxymorphone hydrochloride
US10258583B2 (en) 2014-05-01 2019-04-16 Sun Pharmaceutical Industries Limited Extended release liquid compositions of guanfacine
WO2015166472A1 (en) * 2014-05-01 2015-11-05 Sun Pharmaceutical Industries Limited Extended release liquid compositions of metformin
US11523996B2 (en) 2014-05-01 2022-12-13 Sun Pharmaceutical Industries Limited Extended release liquid compositions of metformin
US11504345B2 (en) 2014-05-01 2022-11-22 Sun Pharmaceutical Industries Limited Extended release liquid compositions of metformin
US9962336B2 (en) 2014-05-01 2018-05-08 Sun Pharmaceutical Industries Limited Extended release suspension compositions
US9962345B2 (en) 2014-05-01 2018-05-08 Sun Pharmaceutical Industries Limited Oral liquid compositions of guanfacine
US10285908B2 (en) 2014-07-30 2019-05-14 Sun Pharmaceutical Industries Ltd Dual-chamber pack
US10226457B2 (en) 2014-10-17 2019-03-12 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US9849124B2 (en) 2014-10-17 2017-12-26 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
US10111839B2 (en) 2014-10-31 2018-10-30 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10507186B2 (en) 2014-10-31 2019-12-17 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10449159B2 (en) 2014-10-31 2019-10-22 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10500162B2 (en) 2014-10-31 2019-12-10 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10512613B2 (en) 2014-10-31 2019-12-24 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10292938B2 (en) 2014-10-31 2019-05-21 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10292939B2 (en) 2014-10-31 2019-05-21 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10512612B2 (en) 2014-10-31 2019-12-24 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10688060B2 (en) 2014-10-31 2020-06-23 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10568841B2 (en) 2014-10-31 2020-02-25 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US11896722B2 (en) 2014-10-31 2024-02-13 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
WO2016087952A1 (en) * 2014-12-05 2016-06-09 Sun Pharmaceutical Industries Limited Gastroretentive extended release suspension compositions
WO2016123202A1 (en) 2015-01-29 2016-08-04 Johnson Matthey Public Limited Company Process of preparing low abuk oxymorphone hydrochloride
US9918979B2 (en) 2015-01-29 2018-03-20 Johnson Matthey Public Limited Company Process of preparing low ABUK oxymorphone hydrochloride
WO2017015309A1 (en) 2015-07-22 2017-01-26 John Hsu Composition comprising a therapeutic agent and a respiratory stimulant and methods for the use thereof
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9943513B1 (en) 2015-10-07 2018-04-17 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US10478429B2 (en) 2015-10-07 2019-11-19 Patheon Softgels, Inc. Abuse deterrent dosage forms
US10238803B2 (en) 2016-05-02 2019-03-26 Sun Pharmaceutical Industries Limited Drug delivery device for pharmaceutical compositions
US10369078B2 (en) 2016-05-02 2019-08-06 Sun Pharmaceutical Industries Limited Dual-chamber pack for pharmaceutical compositions
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
US10646485B2 (en) 2016-06-23 2020-05-12 Collegium Pharmaceutical, Inc. Process of making stable abuse-deterrent oral formulations
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US11590081B1 (en) 2017-09-24 2023-02-28 Tris Pharma, Inc Extended release amphetamine tablets
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US11918689B1 (en) 2020-07-28 2024-03-05 Tris Pharma Inc Liquid clonidine extended release composition

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